Article

Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors.

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Abstract

3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head & neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 T max ̃1.1 hours), an effective median T ½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.

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... TNO155 in combination with KRAS G12C inhibitors exhibited a synergistic effect in KRAS G12C mutant cells and shrank tumors in the KRAS G12C NSCLC PDX preclinical model [121]. According to initial clinical results, TNO155 showed favorable pharmacokinetic properties and safety, but limited efficacy as a single agent in various advanced solid tumors (NCT03114319) [122]. Currently, TNO155 is undergoing clinical trials in combination with other KRAS G12C inhibitors adagrasib (NCT04330664) or JDQ443 (NCT04699188) in advanced solid tumors harboring KRAS G12C mutation [123,124]. ...
... Perhaps, this can be better explained by an indepth study of the function of SHP2 in tumors and its regulatory mechanism in the RTK-RAS-MAPK pathway, with a focus on the distinct roles of scaffolding and phosphatase activity. On the other hand, since the initial results of another SHP2 allosteric inhibitor in advanced solid tumors were not outstanding, it is necessary to find suitable biomarkers in preclinical studies or clinical trials to guide the design of clinical trials [122]. And the combination with other targeted drugs might be an excellent choice, whether to enhance the efficacy or delay drug resistance [122]. ...
... On the other hand, since the initial results of another SHP2 allosteric inhibitor in advanced solid tumors were not outstanding, it is necessary to find suitable biomarkers in preclinical studies or clinical trials to guide the design of clinical trials [122]. And the combination with other targeted drugs might be an excellent choice, whether to enhance the efficacy or delay drug resistance [122]. In addition, SHP2 is a key downstream effector of PD-1 signaling in T cells and several studies have confirmed that SHP2 allosteric inhibitors not only directly inhibit KRAS-driven tumors but also exert anti-tumor immunity in the tumor microenvironment [121,170,171]. ...
Article
Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRASG12C mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy. So far, two small molecule inhibitors sotorasib and adagrasib targeting KRASG12C have received accelerated approval for the treatment of non-small cell lung cancer (NSCLC) harboring KRASG12C mutations. In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRASG12C covalent inhibitors in other KRASG12C-positive malignancies, novel KRAS inhibitors beyond KRASG12C mutation or pan-KRAS inhibitors, and approaches to indirectly targeting KRAS. In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRASG12C mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.
... A SHP2 inhibitor is unlikely to work on its own, however. FIH trials of the first SHP2 inhibitors to enter the clinic (e.g., RMC-4630 and TNO155) clearly showed limited monotherapy activity and were not optimally designed to explore rational combinations (19,20). ...
... All patients in this series unsurprisingly had primary progression on PF-07284892 monotherapy. These findings are consistent with trials of other SHP2 inhibitors in which little singleagent activity was observed (20,22). Furthermore, patients with florid disease progression may clinically deteriorate and miss the opportunity to receive subsequent cancer-directed therapies altogether. ...
... The preclinical and clinical combination therapy activity presented here supports the role of SHP2 as an "Achilles' heel" whose inhibition may sensitize or resensitize diverse tumors to targeted therapy. Of note, although responses to the up-front combination of KRAS G12C and SHP2 inhibitors (e.g., JDQ443 and TNO155 or adagrasib and RMC-4630) have previously been described in KRAS G12C -mutant cancers, the patients had not first received either agent as monotherapy, challenging ascertaining the need for combination treatment (20,23). Our data support combination therapy in other oncogene-driven cancers. ...
Article
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Unlabelled: Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. Significance: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda.
... The phase III KEYNOTE-042 trial that demonstrated an OS benefit of pembrolizumab in the first-line setting versus platinum-based chemotherapy in patients with advanced NSCLC with PD-L1 expression ≥ 1%, evaluated in an exploratory analysis, the association between KRAS status and efficacy to ICPI. KRAS status was determined by whole exome sequencing (WES) of tumor tissue in 301 patients with LUAD of the 1274 randomized participants with NSCLC, being 69 (32). ...
... There are several SHP2 inhibitors in development. RMC-4630 has shown clinical activity with a DCR of 67% for all KRAS mutations, and 75% for KRAS G12C mutations (phase I NCT03989115) (11,58,68,69). TNO155 is a selective, allosteric, oral inhibitor of SHP2 and is being studied in a phase I trial in advanced solid tumors after disease progression following standard therapy (NCT03114319, NCT04330664) (68,69). ...
... RMC-4630 has shown clinical activity with a DCR of 67% for all KRAS mutations, and 75% for KRAS G12C mutations (phase I NCT03989115) (11,58,68,69). TNO155 is a selective, allosteric, oral inhibitor of SHP2 and is being studied in a phase I trial in advanced solid tumors after disease progression following standard therapy (NCT03114319, NCT04330664) (68,69). ...
Article
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Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.
... Emerging efficacy data from the first SHP2 allosteric inhibitors to reach the clinic, RMC-4630 and TNO155, have shown that this mechanism of action is not highly effective on its own as an antitumor agent (110). Aside from one complete response (NF1 LOF uterine carcinoma) and one partial response (KRAS G12C -mutant NSCLC), both treated with RMC-4630, the best tumor responses reported have stable disease (111). ...
... Another open question is related to the chronic tolerability of such combination therapies. The adverse events associated with most of the SHP2i deriving from on-target off-cancer target inhibition include gastrointestinal tract toxicity such as diarrhea, decreased platelets and neutrophils, increased blood creatine phosphokinase, peripheral edema, and acneiform dermatitis (110). Because these side effects partially overlap with the typical toxicity related to inhibitors of the MAPK pathway, they may potentially affect the combinability of these agents. ...
Article
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Unlabelled: The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. Significance: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.
... This study will also include patients with KRAS G12C -mutated NSCLC. Initial results with TNO155 indicated favorable pharmacokinetic properties with rapid absorption and a half-life of 34 hours[96]. AEs were mostly grade 1/2; the most common grade ≥3 AEs were decreased platelets (4%), increased aspartate aminotransferase, diarrhea and decreased neutrophils (each 3%)[96]. The optimal dosing schedule of TNO155 is under investigation.Better together: the need for combination therapyEven if direct inhibitors of mutant KRAS show promising efficacy in clinical trials, they are unlikely to provide enduring benefit if used as monotherapies. ...
... Initial results with TNO155 indicated favorable pharmacokinetic properties with rapid absorption and a half-life of 34 hours[96]. AEs were mostly grade 1/2; the most common grade ≥3 AEs were decreased platelets (4%), increased aspartate aminotransferase, diarrhea and decreased neutrophils (each 3%)[96]. The optimal dosing schedule of TNO155 is under investigation.Better together: the need for combination therapyEven if direct inhibitors of mutant KRAS show promising efficacy in clinical trials, they are unlikely to provide enduring benefit if used as monotherapies. ...
Article
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Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ∼13% of patients. While KRAS was long considered ‘undruggable’, several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.
... In a phase I/II study (NCT03634982) with RMC-4630, including patients with tumors harboring RAS alterations (including KRAS amplification), initial clinical data showed a disease control rate of 71% (5/7 patients) with tumor volume reduction observed in three patients (43%) and a confirmed objective response in one patient with KRASG12C-mutated lung cancer [61]. Initial clinical data in a phase I study (NCT03114319) with the SHP2 inhibitor TNO155 showed sensitivity in some tumors mutated in KRASG12, particularly KRASG12C-mutated lung cancer and BRAF/NRAS mutation-negative melanoma, but no partial responses [62]. SOS1 inhibitors block the interaction between SOS1 and KRAS-GDP, preventing nucleotide exchange and GTP loading of KRAS [57]. ...
Article
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Simple Summary Colorectal cancer (CRC) is a deadly disease in which KRAS mutations are prevalent and are associated with poor prognosis. The emergence of KRAS inhibitors is a promising treatment option. This review discusses various classes of KRAS inhibitors, that can be used alone or combined to overcome resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of various strategies to target KRAS in CRC. Abstract Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with significant public health concerns. This review examines the landscape of KRAS inhibition in colorectal cancer (CRC), focusing on recent advances in therapeutic strategies targeting this oncogene. Historically deemed undruggable due to its complex structure and essential role in tumorigenesis, KRAS mutations are prevalent in CRC and are associated with poor prognosis. However, breakthroughs in drug development have led to the emergence of KRAS inhibitors as promising treatment options. This review discusses various classes of KRAS inhibitors, including covalent and non-covalent inhibitors, as well as combination therapies aimed at enhancing efficacy and overcoming resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of KRAS inhibitors either as monotherapy or in combination with other agents, such as anti-EGFR antibodies. Despite challenges such as resistance mechanisms and tumor heterogeneity, the development of KRAS inhibitors represents a significant advance in CRC treatment and holds promise for improving patient outcomes in the future.
... SHP099 is the first allosteric inhibitor of SHP2, which suppresses RTK-driven cancers by inhibiting RAS-ERK signaling 14 . Considering the limited efficacy of SHP2 inhibitor monotherapy, most current studies for the treatment of solid tumors adopt combination therapies 15 . Studies have shown that co-inhibition of SHP2 and MAPK pathway signaling such as EGFR, KRAS, and MEK effectively inhibits cancer cell growth and counters adaptive cancer resistance [16][17][18][19][20] . ...
Article
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Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.
... Recently reported data from early phase clinical trials demonstrate only modest activity of monotherapy in tumors with varied KRAS alterations. For example, in a phase 1 trial evaluating the SHP2 inhibitor TNO155, the best observed response was SD, observed in only 20% of patients (NCT03114319) [88][89][90] . ...
Article
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RAS family variants-most of which involve KRAS-are the most commonly occurring hotspot mutations in human cancers and are associated with a poor prognosis. For almost four decades, KRAS has been considered undruggable, in part due to its structure, which lacks small-molecule binding sites. But recent developments in bioengineering, organic chemistry and related fields have provided the infrastructure to make direct KRAS targeting possible. The first successes occurred with allele-specific targeting of KRAS p.Gly12Cys (G12C) in non-small cell lung cancer, resulting in regulatory approval of two agents-sotorasib and adagrasib. Inhibitors targeting other variants beyond G12C have shown preliminary antitumor activity in highly refractory malignancies such as pancreatic cancer. Herein, we outline RAS pathobiology with a focus on KRAS, illustrate therapeutic approaches across a variety of malignancies, including emphasis on the 'on' and 'off' switch allele-specific and 'pan' RAS inhibitors, and review immunotherapeutic and other key combination RAS targeting strategies. We summarize mechanistic understanding of de novo and acquired resistance, review combination approaches, emerging technologies and drug development paradigms and outline a blueprint for the future of KRAS therapeutics with anticipated profound clinical impact.
... Clinical efficacy has been documented with TNO155, a pyrazine allosteric SHP2 inhibitor. In a phase I dose-finding study, 118 patients with advanced solid tumors were treated with TNO-155 with 20% experiencing stable disease (105). Preliminary results from the FLAGSHP-1 study, analyzing the SHP2 inhibitor ERAS-601 in advanced solid tumors were disappointing, with a partial response seen in 1/27 patients treated (106). ...
Article
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Targeting the RAS pathway remains the holy grail of precision oncology. In the case of pancreatic ductal adenocarcinomas (PDAC), 90–92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling. The smooth structure of the altered KRAS protein without a binding pocket and its affinity for GTP have, in the past, hampered drug development. The emergence of KRASG12C covalent inhibitors has provided renewed enthusiasm for targeting KRAS. The numerous pathways implicated in RAS activation do, however, lead to the development of early resistance. In addition, the dense stromal niche and immunosuppressive microenvironment dictated by oncogenic KRAS can influence treatment responses, highlighting the need for a combination-based approach. Given that mutations in KRAS occur early in PDAC tumorigenesis, an understanding of its pleiotropic effects is key to progress in this disease. Herein, we review current perspectives on targeting KRAS with a focus on PDAC.
... A further key consideration for the development and use of any novel drug is toxicity. Allosteric PTPN11 inhibitors appear to have an acceptable toxicity profile in stage 1 clinical trials, although further dose escalation studies are ongoing [49,126]. Of note, trials assessing the efficacy of several PTPN1 inhibitors for the treatment of type 2 diabetes were halted due to low efficacy and toxicities, including vomiting and diarrhoea [127,128]. ...
Article
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Advances in immunotherapy have brought significant therapeutic benefits to many cancer patients. Nonetheless, many cancer types are refractory to current immunotherapeutic approaches, meaning that further targets are required to increase the number of patients who benefit from these technologies. Protein tyrosine phosphatases (PTPs) have long been recognised to play a vital role in the regulation of cancer cell biology and the immune response. In this review, we summarize the evidence for both the pro-tumorigenic and tumour-suppressor function of non-receptor PTPs in cancer cells and discuss recent data showing that several of these enzymes act as intracellular immune checkpoints that suppress effective tumour immunity. We highlight new data showing that the deletion of inhibitory PTPs is a rational approach to improve the outcomes of adoptive T cell-based cancer immunotherapies and describe recent progress in the development of PTP inhibitors as anti-cancer drugs.
... In addition, this combination is already under investigation in an ongoing trial (NCT04000529), and data to support the clinical safety profile of TNO155 and ribociclib are expected to result soon. Single-agent TNO155 has been reported to be well-tolerated in patients with solid tumors, with the majority of reported adverse events being grade 1 or 2 and consistent with anticipated on-target effects of SHP2 inhibition (53). Our evidence is in favor of the advancement of novel SHP2i into clinical trials for the treatment of patients with MPNST. ...
Article
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Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.
... Historically, SHP2 has been an elusive molecular target; however, the advent of allosteric inhibitors has allowed for the development of TNO155, an orally bioavailable, first-in-class allosteric inhibitor of SHP2, to be examined in patients with advanced solid tumors, including BRAF/NRAS wild-type melanoma. Preliminary results from a firstin-human dose-escalation trial demonstrated that TNO155 inhibited SHP2 activity at well-tolerated doses [72]. This study is still actively recruiting patients, with anticipated completion in early 2024 (NCT03114319). ...
Article
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Simple Summary Immune checkpoint inhibitors and BRAF/MEK inhibitors are the cornerstone of treatment for melanoma; however, primary and acquired resistance to these therapies highlight an ongoing, unmet need to develop novel treatment modalities. The emergence of monoclonal antibodies and small molecules as therapeutic platforms permits the targeting of specific mediators that drive the cancer phenotype. Melanoma represents a disease in which several driver mutations have been discovered, yet only a few effective targeted therapies exist. The effective targeting of these molecules may be the key to unlocking several potential novel therapies. Here we review the persisting efforts to identify and exploit molecular targets to optimize clinical outcomes for patients with melanoma. Abstract It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting the BRAFV600 mutations found in 40–50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited to BRAFV600 melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAFV600 melanoma.
... Different SHP2 inhibitors have been specifically designed to overcome resistance to RTK-and MAPK-targeted agents, including TNO155 or RMC-4630. In both cases, recently reported dose-escalation data have shown limited activity in monotherapy, which contrasts with the large number of patients treated (5,6). Overall, this underscores the necessity of novel patient-centric clinical trial designs to preclude and minimize the exposure of patients to subtherapeutic doses or agents with limited monotherapy activity. ...
Article
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A disruptive clinical trial design allowed Drilon and colleagues to demonstrate proof of concept of the potential of PF-07284892 to overcome resistance mechanisms to targeted therapies in the clinic. See related article by Drilon et al. (7).
... Because of promising preclinical results, the first clinical trials are currently ongoing. These indicate that SHP2 inhibitors have a manageable toxicity profile with increased creatine phosphokinase, peripheral edema, diarrhea, and acneiform dermatitis and decreased ejection fraction as the most reported adverse events [77]. ...
Article
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Opinion statement One of the great challenges in digestive oncology is choosing the optimal therapy for RAS-mutated metastatic colorectal cancer (mCRC). Even though the RAS genes and accompanying pathway were identified decades ago and extensive knowledge exists on their role in carcinogenesis, it has proven challenging to translate these insights into new therapies and clinical benefit for patients. However, recently, new drugs targeting this pathway (for example, KRASG12C inhibitors) have shown promising results in clinical trials, as monotherapy or in combination regimens. Although resistance remains an important issue, more knowledge on adaptive resistance and feedback loops in the RAS-pathway has led to strategical combination regimens to overcome this problem. In the past year, many encouraging results have been published or presented at conferences. Even though some of the data is still preliminary, these studies may bring practice-changing results and can lead to a clinical benefit for patients over the coming years. Because of these recent developments, the treatment of RAS-mutated mCRC has become a topic of great interest. Therefore, in this review, we will summarize the standard of care and discuss the most important emerging therapies for this patient population.
... The SHP2 inhibitor TNO155 is being studied in a phase I study in advanced tumors, including KRAS G12C-mutant NSCLC (NCT03114319). Preliminary results suggest favorable pharmacokinetics and safety profile, with AEs mostly of grade 1 and 2 (99). Preclinical data suggest combined KRAS G12C and SHP2 inhibition may lead to improved clinical efficacy in KRAS G12C mutant-NSCLC (88,89). ...
Article
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Background and objective: Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. Methods: In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. Key content and findings: KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. Conclusions: The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes.
... 302 308 Additionally, after promising initial safety and tolerability were reported for SHP2 inhibitor TNO155, multiple clinical trials are being conducted the drug in combination with other therapies. 309 Table 4 below provides a list of ongoing clinical trials targeting KRAS and its upstream and downstream pathways. ...
Article
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with a high rate of recurrence and a dismal 5‐year survival rate. Contributing to the poor prognosis of PDAC is the lack of early detection, a complex network of signaling pathways and molecular mechanisms, a dense and desmoplastic stroma, and an immunosuppressive tumor microenvironment. A recent shift toward a neoadjuvant approach to treating PDAC has been sparked by the numerous benefits neoadjuvant therapy (NAT) has to offer compared with upfront surgery. However, certain aspects of NAT against PDAC, including the optimal regimen, the use of radiotherapy, and the selection of patients that would benefit from NAT, have yet to be fully elucidated. This review describes the major signaling pathways and molecular mechanisms involved in PDAC initiation and progression in addition to the immunosuppressive tumor microenvironment of PDAC. We then review current guidelines, ongoing research, and future research directions on the use of NAT based on randomized clinical trials and other studies. Finally, the current use of and research regarding targeted therapy for PDAC are examined. This review bridges the molecular understanding of PDAC with its clinical significance, development of novel therapies, and shifting directions in treatment paradigm. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with a high rate of recurrence and a dismal 5‐year survival rate. A recent shift toward a neoadjuvant approach to treating PDAC has been sparked by the numerous benefits neoadjuvant therapy (NAT) has to offer compared with upfront surgery. This review bridges the molecular understanding of PDAC with its clinical significance, development of novel therapies, and shifting directions in treatment paradigm with an emphasis on the use of NAT.
... This is likely because 91% of the cell lines included in our analysis are either European or East Asian. Interestingly, several ancestry-associated dependencies related to genes related to tyrosine-kinase signaling including PTPN11 (which encodes SHP2), which is a therapeutic target being tested in clinical trials 13 , and its complex member GRB2 [Supplemental Figure 1]. ...
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Reducing disparities is critical to promote equity of access to precision treatments for all patients with cancer. While socioenvironmental factors are a major driver behind such disparities, biological differences also are likely to contribute. The prioritization of cancer drug targets is foundational for drug discovery, yet whether ancestry-related signals in target discovery pipelines exist has not been systematically explored due to the absence of data at the appropriate scale. Here, we analyzed data from 611 genome-scale CRISPR/Cas9 viability experiments in human cell line models as part of the Cancer Dependency Map to identify ancestry-associated genetic dependencies. Surprisingly, we found that most putative associations between ancestry and dependency arose from artifacts related to germline variants that are present at different frequencies across ancestry groups. In 2-5% of genes profiled in each cellular model, germline variants in sgRNA targeting sequences likely reduced cutting by the CRISPR/Cas9 nuclease. Unfortunately, this bias disproportionately affected cell models derived from individuals of recent African descent because their genomes tended to diverge more from the consensus genome typically used for CRISPR/Cas9 guide design. To help the scientific community begin to resolve this source of bias, we report three complementary methods for ancestry-agnostic CRISPR experiments. This report adds to a growing body of literature describing ways in which ancestry bias impacts cancer research in underappreciated ways.
... Before achieving an active state, a structural alternation is required for SHP2 to release its PTP catalytic domain from auto-inhibitory interaction with its N-SH2 domain (10,27,28). Hence, SHP2 can be pharmacologically inhibited by allosteric binders, including SHP099 and TNO155, which stabilize SHP2 in its inactive form (29,30). Systemic administration of these SHP2 inhibitors showed promising anti-tumor effects, and some active clinical trials with SHP2 inhibitors have recently emerged (31)(32)(33)(34). ...
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SH2 containing protein tyrosine phosphatase-2 (SHP2) is recognized as a druggable oncogenic phosphatase that is expressed in both tumor cells and immune cells. How tumor cell–autonomous SHP2 contributes to an immunosuppressive tumor microenvironment (TME) and therapeutic failure of immune checkpoint blockades in metastatic breast cancer (MBC) is not fully understood. Herein, we utilized systemic SHP2 inhibition and inducible genetic depletion of SHP2 to investigate immune reprogramming during SHP2 targeting. Pharmacologic inhibition of SHP2 sensitized MBC cells growing in the lung to α-programmed death ligand 1 (α-PD-L1) antibody treatment via relieving T-cell exhaustion induced by checkpoint blockade. Tumor cell–specific depletion of SHP2 similarly reduced pulmonary metastasis and also relieved exhaustion markers on CD8+ and CD4+ cells. Both systemic SHP2 inhibition and tumor cell–autonomous SHP2 depletion reduced tumor-infiltrated CD4+ T cells and M2-polarized tumor-associated macrophages. Analysis of TCGA datasets revealed that phosphorylation of SHP2 is important for immune-cell infiltration, T-cell activation and antigen presentation. To investigate this mechanistically, we conducted in vitro T-cell killing assays, which demonstrated that pretreatment of tumor cells with FGF2 and PDGF reduced the cytotoxicity of CD8+ T cells in a SHP2-dependent manner. Both growth factor receptor signaling and three-dimensional culture conditions transcriptionally induced PD-L1 via SHP2. Finally, SHP2 inhibition reduced MAPK signaling and enhanced STAT1 signaling, preventing growth factor–mediated suppression of MHC class I. Overall, our findings support the conclusion that tumor cell–autonomous SHP2 is a key signaling node utilized by MBC cells to engage immune-suppressive mechanisms in response to diverse signaling inputs from TME. Significance Findings present inhibition of SHP2 as a therapeutic option to limit breast cancer metastasis by promoting antitumor immunity.
... TNO155 is a further SHP2 inhibitor in a phase I study in patients with advanced solid cancers in selected indications (also patients with KRAS G12C-mutated NSCLC) (NCT03114319). Initial results indicate favourable pharmacokinetic properties, with mainly grade 1 and 2 adverse events and among grade ≥3 adverse events in particular thrombocytopenia, increased AST, diarrhoea and neutropenia (53). Table 2 lists the clinical trials described with direct and indirect inhibitors of KRAS. ...
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Background and objective: The genetic nature of cancer provides the rationale to support the need for molecular diagnosis and patient selection for individualised antineoplastic treatments that are the best in both tolerability and efficacy for each cancer patient, including non-small cell lung cancer (NSCLC) patients. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations represent the prevalent oncogenic driver in NSCLC, being detected in roughly one-third of cases and KRAS G12C is the most frequent mutation found in approximately 13% of patients. Methods: This paper gives an overview of the numerous scientific efforts in recent decades aimed at KRAS inhibition. Key content and findings: Sotorasib is the first approved KRAS G12C inhibitor that has been shown to provide a durable clinical benefit in patients with pre-treated NSCLC with KRAS G12C mutation. Together with the development of new targeted drugs, the development of strategies to control resistance mechanisms is one of the major drivers of research that is exploring the use of KRAS inhibitors not only alone, but also in combination with other targeted therapies, chemotherapy and immunotherapy. Conclusions: This review will describe the major therapeutic developments in KRAS mutation-dependent NSCLC and will analyse future perspectives to maximise benefits for this group of patients.
... TNO155, another SHP2 inhibitor, 68 has promising early safety and tolerability as a single agent in solid tumors with expected dependency on RTKs, and it is being evaluated in combination with other agents, including KRAS G12C inhibitors, and osimertinib, with more data forthcoming. 69 BI 1701963 is a small-molecule inhibitor that prevents KRAS activation through binding of SOS1. It has been evaluated as monotherapy and in combination with trametinib in KRAS-mutated solid tumors and has generally been well tolerated and has shown signs of RAS/MAPK signaling inhibition, with more data anticipated. ...
Article
Despite the discovery of RAS oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against RAS has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as EGFR, ALK, and ROS1. The discoveries that (1) malignant RAS oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of KRAS G12C in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward KRAS-driven cancers. Although the development of allele-selective KRAS G12C inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers. Heterogeneous resistance mechanisms generally result in the restoration of RAS/mitogen-activated protein kinase pathway signaling. Many approaches are being evaluated to overcome this resistance, with many combinatorial clinical trials ongoing. Furthermore, because KRAS G12D and KRAS G12V are more prevalent than KRAS G12C , there remains an unmet need for additional therapeutic strategies for these patients. Thus, our current translational standing could be described as “the end of the beginning,” with additional discovery and research innovation needed to address the enormous disease burden imposed by RAS-mutant cancers. Here, we describe the development of KRAS G12C inhibitors, the challenges of resistance to these inhibitors, strategies to mitigate that resistance, and new approaches being taken to address other RAS-mutant cancers.
... Notably, results of phase 1 first-in-human clinical trial showed that RMC-4630 led to a disease control rate of 71% in KRAS G12C mutated NSCLC patients (n=19), as a single-agent monotherapy (124). Likewise, TNO-155 is currently being tested in a phase 1 dose escalation/ expansion trial (NCT03114319) in adults with advanced solid tumors alone (125) or in combination with JDQ443 (KRAS G12C inhibitor), in KRAS G12C patients with advanced solid tumors (NCT04699188). ...
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Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.
... SHP2 inhibitor enhanced the efficacy of α-PD-1 in murine tumor models [252][253][254]. A clinical study exploring SHP2 inhibitor combined with α-PD-1 is still ongoing (NCT04000529), and the final data of this combination study are not yet available [255]. ...
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Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.
... In a Phase I/II study (NCT03634982) with RMC-4630, that included patients with tumors harboring RAS node alterations (KRAS G12mut , KRAS amp , NF1 LOF , BRAF class3 ), first clinical data demonstrated a disease control rate of 71% (5/7) with reduction in tumor volume reported in three (43%) and one confirmed objective response in patients with KRAS G12C mutant nonsmall cell lung cancer (38). First clinical data in a Phase I clinical study (NCT03114319) with the SHP2 inhibitor TNO155 showed sensitivity of some KRAS G12 -mutant tumors, especially KRAS G12C -mutant NSCLC and BRAF/NRAS wild-type melanoma, but in the absence of partial responses (39). ...
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KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, and KRASG12A-mutant or KRAS wild-type-amplified cancers, as well as cancers with acquired resistance to KRASG12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility. Significance: Mutant-selective KRASG12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.
... In this study, 118 patients with a variety of pre-treated solid tumours received variable dosing schedules of TNO155. Favourable pharmacokinetic properties and promising early safety and tolerability data were seen [54]. There is also an ongoing treatment arm of TNO155 in combination with nazartinib (mutant-selective EGFR inhibitor) in patients with EGFRmutant NSCLC (NCT03114319). ...
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Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently mutated in aggressive advanced solid tumours, particularly colorectal, lung and pancreatic cancer. Since the first mutated KRAS was discovered in the 1980s, decades of research to develop targeted inhibitors of mutant KRAS have fallen short of the task, until recently. Multiple agents are now in clinical trials, including specific mutant KRAS inhibitors, pan-KRAS inhibitors, therapeutic vaccines and other targeted inhibitors. Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.
... Several other novel compounds are currently under active evaluation to understand differences in terms of potency and on target resistance (Table 1) 28,[37][38][39][40][41][42][43][44][45] . A modification to the ARS-1620 molecule has been brought forward as JNJ-74699147 and entered clinical development in July 2019 by Janssen. ...
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Cancers harboring mutations in the Kirsten rat sarcoma homolog (KRAS) gene have been associated with poor prognosis and lack of targeted therapies. KRAS mutations occur in approximately one in four patients diagnosed with non-small cell lung cancer (NSCLC) with KRAS G12C mutations harbored at approximately 11–16%. Research into KRAS-driven tumors and analytical chemistry have borne a new class of selective small molecules against the KRAS G12C isoform. Phase II data for sotorasib (AMG510) has demonstrated a 37.1% overall response rate (ORR). Adagrasib (MRTX849) has demonstrated a 45% ORR in an early study. While single agent efficacy has been seen, initial data suggest combination approaches are an opportunity to improve outcomes. Here, we present perspectives on the initial progress in targeting KRAS G12C, examine co-mutations evident in KRAS G12C NSCLC, and comment on potential future combinatorial approaches including SHP2, SOS1, MEK, EGFR, mTOR, CDK, and checkpoint blockade which are currently being evaluated in clinical trials. As of May 28, 2021, sotorasib has achieved US FDA approval for patients with KRAS G12C mutant lung cancer after one line of a prior therapy.
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Among the most common molecular alterations detected in non-small-cell lung cancer (NSCLC) are mutations in Kristen Rat Sarcoma viral oncogene homolog (KRAS). KRAS mutant NSCLC is a heterogenous group of diseases, different from other oncogene-driven tumors in terms of biology and response to therapies. Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRASG12C has revolutionized the treatment of KRASG12C-mutated NSCLC patients. Sotorasib and adagrasib, direct KRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRASG12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment in KRASG12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment with KRASG12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. New KRASG12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRASG12C-mutated NSCLC.
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The development of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors is a hot spot in the research and development of antitumor drugs, which may induce immunomodulatory effects in the tumor microen-vironment and participate in anti-tumor immune responses. To date, several SHP2 inhibitors have made remarkable progress and entered clinical trials for the treatment of patients with advanced solid tumors. Multiple compounds derived from natural products have been proved to influence tumor cell proliferation, apoptosis, migration and other cellular functions, modulate cell cycle and immune cell activation by regulating the function of SHP2 and its mutants. However, there is a paucity of information about their diversity, biochemistry, and therapeutic potential of targeting SHP2 in tumors. This review will provide the structure, classification, inhibitory activities, experimental models, and antitumor effects of the natural products. Notably, this review summarizes recent advance in the efficacy and pharmacological mechanism of natural products targeting SHP2 in inhibiting the various signaling pathways that regulate different cancers and thus pave the way for further development of anticancer drugs targeting SHP2.
Introduction: Treatment resistance poses a significant obstacle in oncology, especially in biliary tract cancer (BTC) and pancreatic cancer (PC). Current therapeutic options include chemotherapy, targeted therapy, and immunotherapy. Resistance to these treatments may arise due to diverse molecular mechanisms, such as genetic and epigenetic modifications, altered drug metabolism and efflux, and changes in the tumor microenvironment. Identifying and overcoming these mechanisms is a major focus of research: strategies being explored include combination therapies, modulation of the tumor microenvironment, and personalized approaches. Areas covered: We provide a current overview and discussion of the most relevant mechanisms of resistance to chemotherapy, target therapy, and immunotherapy in both BTC and PC. Furthermore, we compare the different strategies that are being implemented to overcome these obstacles. Expert opinion: So far there is no unified theory on drug resistance and progress is limited. To overcome this issue, individualized patient approaches, possibly through liquid biopsies or single-cell transcriptome studies, are suggested, along with the potential use of artificial intelligence, to guide effective treatment strategies. Furthermore, we provide insights into what we consider the most promising areas of research, and we speculate on the future of managing treatment resistance to improve patient outcomes.
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Activation of effector T cells leads to upregulation of PD-1, which can inhibit T cell activity following engagement with its ligand PD-L1. Post-translational modifications (PTMs), including glycosylation, phosphorylation, ubiquitination, and palmitoylation, play a significant role in regulating PD-1 protein stability, localization, and inter-protein interactions. Targeting PTM of PD-1 in T cells has emerged as a potential strategy to overcome PD-1-mediated immunosuppression in cancer and enhance antitumor immunity. The regulatory signaling pathways that induce PTM of PD-1 can be suppressed with small-molecule inhibitors, and monoclonal antibodies can directly target PD-1 PTMs. Preliminary outcomes from exploratory studies suggest that focusing on the PTM of PD-1 has strong therapeutic potential and can enhance the response to anti-PD-1.
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Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development. Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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In locally advanced and metastatic pancreatic cancers, germline sequencing, somatic mutation and fusion testing, and testing for microsatellite instability or mismatch repair are recommended to identify patients who are candidates for targeted therapies or immune checkpoint inhibitors, either as current standard therapy or on a biomarker-driven clinical trial. Biomarkers that impact current standard treatments include germline BRCA1/2 mutation, microsatellite instability or mismatch repair deficiency, BRAF V600E mutation, NTRK1/2/3 fusion, and RET fusion. However, each of these aberrations forms a small minority of patients with pancreatic cancer. The most common driver mutation in pancreatic cancer is an oncogenic KRAS mutation, found in over 90% of patients, and though this is not currently targetable with standard therapy, multiple efforts to effectively target KRAS are underway. In particular, about 1% of patients have pancreatic cancers harboring KRAS G12C mutations, for which KRAS G12C-specific small molecule inhibitors are in clinical trials with promising early data. KRAS wild-type pancreatic cancers, while comprising a minority of pancreatic cancer patients, are more likely to arise among younger patients and are enriched for other potentially targetable driver mutations, including BRAF mutations and activating deletions, BRAF or RAF1 fusions, and additional aberrations, including gene fusions involving NRG1, FGFR1/2/3, NTRK1/2/3, or RET. Emerging potential biomarkers with novel targeted therapies in development include claudin 18.2 expression and MTAP deletion.
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Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.
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Introduction: The protein tyrosine phosphatase SHP2 (PTPN11) is a negative regulator of glycoprotein VI (GPVI)-induced platelet signal under certain conditions. Clinical trials with derivatives of the allosteric drug SHP099, inhibiting SHP2, are ongoing as potential therapy for solid cancers. Gain-of-function mutations of the PTPN11 gene are observed in part of the patients with the Noonan syndrome, associated with a mild bleeding disorder. Assessment of the effects of SHP2 inhibition in platelets from controls and Noonan syndrome patients. Materials and methods: Washed human platelets were incubated with SHP099 and stimulated with collagen-related peptide (CRP) for stirred aggregation and flow cytometric measurements. Whole-blood microfluidics assays using a dosed collagen and tissue factor coating were performed to assess shear-dependent thrombus and fibrin formation. Effects on clot formation were evaluated by thromboelastometry. Results: Pharmacological inhibition of SHP2 did not alter GPVI-dependent platelet aggregation under stirring, but it enhanced integrin αIIbβ3 activation in response to CRP. Using whole-blood microfluidics, SHP099 increased the thrombus buildup on collagen surfaces. In the presence of tissue factor and coagulation, SHP099 increased thrombus size and reduced time to fibrin formation. Blood from PTPN11-mutated Noonan syndrome patients, with low platelet responsiveness, after ex vivo treatment with SHP099 showed a normalized platelet function. In thromboelastometry, SHP2 inhibition tended to increase tissue factor-induced blood clotting profiles with tranexamic acid, preventing fibrinolysis. Conclusion: Pharmacological inhibition of SHP2 by the allosteric drug SHP099 enhances GPVI-induced platelet activation under shear conditions with a potential to improve platelet functions of Noonan syndrome patients.
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SIPRα on macrophages binds with CD47 to resist pro-engulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here we reported that the CD47/SIRPα axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, SHP2 is constitutively neddylated on K358 and K364 sites, thus its auto-inhibited conformation is maintained. In response to CD47-liganded SIRPα, SHP2 is deneddylated by SENP8, which leads to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that the supplementation with SHP2 allosteric inhibitors sensitized the immune treatment-resistant CRC to immunotherapy. Our results emphasized that the CRC subtype which is unresponsive to immunotherapy relies on SIRPαhiSHP2hiNEDD8lo TIMs, and highlighted the need to further combine the strategy of SHP2 targeting in colorectal cancer therapy.
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The development of selective KRASG12C inhibitors that directly inhibit KRAS, an oncogene historically thought to be “undruggable,” represents a watershed moment in oncology and developmental therapeutics. Now, as KRAS-targeted therapy moves into its second phase, there is significant excitement and anticipation for durable disease control in tumor types where options remain limited, with clinical trials testing combination therapies, indirect pan-RAS/MAP kinase pathway inhibitors, and active-state RAS(on) inhibitors. However, there is also reason for caution regarding the safety and tolerability of expanded RAS inhibition. This is evidenced by the intolerability of some combination therapies with selective KRASG12C inhibitors and foreshadowed by prior failures of combination therapies in other oncogene-driven tumors. Herein, we review the landscape of and outlook for KRAS-targeted therapies. We specifically focus upon strategies to combat resistance to KRAS-targeted therapies, and discuss the possibility of off-target or unanticipated on-target effects that may limit clinical use.
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Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors. Significance: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.
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