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The frequency of RAS mutations in human cancers. The data come from TCGA PanCancer Atlas Studies. The activating mutations of RAS occur predominantly at codons 12, 13, and 61 and kirsten‐RAS (KRAS) has the most tendency to be mutated in the three paralogs. Clinically, RAS mutations are most prevalent in pancreatic adenocarcinoma (PC) (70%), colorectal cancer (CRC) (40%), and non‐small cell lung cancer (NSCLC) (30%). (A) PC; (B) colorectal adenocarcinoma; (C) lung adenocarcinoma; (D) uterine corpus endometrial adenocarcinoma; (E) uterine carcinosarcoma; (F) stomach adenocarcinoma; (G) testicular germ cell tumors; (H) cholangiocarcinoma; (I) cervical squamous cell carcinoma; (J) skin cutaneous melanoma; (K) acute myeloid leukemia; (L) thyroid carcinoma; (M) pheochromocytoma and paraganglioma; (N) thymoma.
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Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS)G12C inhibitor that RAS gets rid of the title "undruggable". It is worth noting that the therapeutic effect of KRASG12C inhibitors on differ...
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Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis th...
Citations
... Given the prevalence of RAS mutations and their impact on distant metastasis and mortality, developing effective targeted therapies against RAS or its downstream effectors could significantly improve outcomes for a substantial proportion of thyroid cancer patients [37]. While RAS itself has historically been considered "undruggable," recent advances in targeted therapies, including those targeting downstream effectors of RAS, offer promising avenues for exploration in thyroid cancer [38]. ...
... Notably, ulixertinib has been found to be effective in several models showing intrinsic or acquired resistance to other MAPK pathway inhibitors [138] . Moreover, the combination of ERK inhibitors with upstream inhibitors exhibits synergistic benefits [141][142][143]. Selective inhibitors of JNK signaling, including Feng et al. ...
Lipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent a complex group of biomolecules that not only compose the essential components of biological membranes and act as an energy source, but also function as messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays a crucial role in acquiring lipids to meet the demands of rapid growth. Increasing evidence has suggested that dysregulated lipid metabolism serves as a driver of cancer progression. Posttranslational modifications (PTMs), which occurs in most eukaryotic proteins throughout their lifetimes, affect the activity, abundance, function, localization, and interactions of target proteins. PTMs of crucial molecules are potential intervention sites and are emerging as promising strategies for the cancer treatment. However, there is limited information available regarding the PTMs that occur in cancer lipid metabolism and the potential treatment strategies associated with these PTMs. Herein, we summarize current knowledge of the roles and regulatory mechanisms of PTMs in lipid metabolism. Understanding the roles of PTMs in lipid metabolism in cancer could provide valuable insights into tumorigenesis and progression. Moreover, targeting PTMs in cancer lipid metabolism might represent a promising novel therapeutic strategy.
... RAS mutations result in the activation of MEK kinase, however, clinical trials utilizing single-agent MEK inhibitors for this type of cancer have failed [16,17]. Preclinical studies suggest that the escape from MEK down-regulation may be due to autophagy activation [18]. As a result, several case studies demonstrated that combined inhibition of MEK kinase and autophagy may result in the shrinkage of RAS-mutated tumors, although negative results have been published as well [18][19][20]. ...
... Preclinical studies suggest that the escape from MEK down-regulation may be due to autophagy activation [18]. As a result, several case studies demonstrated that combined inhibition of MEK kinase and autophagy may result in the shrinkage of RAS-mutated tumors, although negative results have been published as well [18][19][20]. This report describes a young woman with metastatic NRAS-positive iCCA, who had a remarkable response to a combined second-line therapy with MEK1/2 inhibitor trametinib, autophagy inhibitor hydroxychloroquine, and anti-angiogenic antibody bevacizumab. ...
Systemic chemotherapy is the main treatment option for patients with advanced intrahepatic cholangiocarcinoma (iCCA), however, its efficacy is limited. Herein, we report a young patient with NRAS-mutated chemoresistant metastatic iCCA, who received second-line therapy with a combination of trametinib (MEK1/2 inhibitor), hydroxychloroquine (autophagy inhibitor), and bevacizumab (angiogenesis inhibitor). A significant response was achieved during therapy, resulting in a 25% decrease in the size of tumor lesions after 2 months of treatment and an improvement in the patient’s condition. The duration of this response was 4 months, but the patient died 10 months after the initiation of this triple therapy. This case report and the analysis of other available studies warrant further investigations on combined MEK and autophagy inhibition in RAS-mutated tumors.
... The function of RAS protein is controlling the signal transduction [21][22][23][24] by acting as molecular switches of cycling through alternating between off (inactive form) when bound to the nucleotide guanosine diphosphate (GDP) and on (active form) when bound to guanosine triphosphate (GTP) [25][26][27][28]. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) play an important role in these two states of the cycle [29][30][31]. ...
RAS (rat sarcoma) oncoproteins are crucial for the growth of some human cancers, including lung, colorectal, and pancreatic adenocarcinomas. The RAS family contains three known human isoforms H(Harvey)-RAS, N(Neuroblastoma)-RAS, and K(Kirsten)-RAS. Mutations in RAS proteins cause up to ~ 30% of cancer cases. For almost 30 years, mutant proteins druggable pockets remained undiscovered, they are nearly identical to their essential, wild-type counterparts and cause cancer. Recent research has increased our knowledge of RAS’s structure, processing, and signaling pathways and revealed novel insights into how it works in cancer cells. We highlight several approaches that inhibit RAS activity with small compounds in this review: substances that blocked farnesyltransferase (FTase), isoprenylcysteine carboxyl methyltransferase (Icmt), and RAS-converting enzyme 1 (Rce1) three important enzymes required for RAS localization. Inhibitors block the son of sevenless (SOS) protein’s role in nucleotide exchange activity, small molecules that interfered with the phosphodiesterase (PDEδ)-mediated intracellular RAS transport processes, substances that focused on inhibiting RAS–effector interactions. Inhibitors are made to suppress the oncogenic K-RAS G12C mutant only when the nucleophilic cysteine residue at codon 12 is present and many inhibitors with various mechanisms like breaking the organization membrane of K-RAS nano-clustering. So, this is a thorough analysis of the most recent advancements in K-RAS-targeted anticancer techniques, hopefully offering insight into the field’s future.
... In the first case, imatinib exerts its therapeutic effect by binding to the ATP-binding site of the hyper-activated mutated c-kit protein in exon 11, preventing its activity and inhibiting downstream signaling pathways [96]. In the second case, inhibitors (sotorasib and adagrasib) bind to the inactive GDP-bound form of KRAS p.G12C, locking it in an inactive state, unable to activate intracellular signals [97]. However, it is true that not all solid tumors with c-kit exon 11 or KRAS p.G12C mutations respond brilliantly to therapy. ...
Simple Summary
Cancer is a complex illness marked by aberrant cellular behaviors and genetic variances, resulting in tumor heterogeneity that presents challenges in cancer prognosis and treatment. This review underscores the significance of comprehending tumor heterogeneity, offering perspectives on its attributes and the intricacies involved in its quantification. By emphasizing the need for effective therapies targeting tumor heterogeneity, this work contributes to raising awareness about this elusive characteristic of cancer.
Abstract
Cancer manifests as a multifaceted disease, characterized by aberrant cellular proliferation, survival, migration, and invasion. Tumors exhibit variances across diverse dimensions, encompassing genetic, epigenetic, and transcriptional realms. This heterogeneity poses significant challenges in prognosis and treatment, affording tumors advantages through an increased propensity to accumulate mutations linked to immune system evasion and drug resistance. In this review, we offer insights into tumor heterogeneity as a crucial characteristic of cancer, exploring the difficulties associated with measuring and quantifying such heterogeneity from clinical and biological perspectives. By emphasizing the critical nature of understanding tumor heterogeneity, this work contributes to raising awareness about the importance of developing effective cancer therapies that target this distinct and elusive trait of cancer.
... These downstream effectors represent only a fraction of the intricate network of signaling pathways regulated by RAS. The complexity and diversity of RAS signaling indicate its fundamental importance in cellular physiology and its role in various diseases, particularly cancer (87,88). ...
Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered “undruggable”, recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.
Liver cirrhosis is a critical stage in the progression of various chronic liver diseases, often leading to severe complications such as ascites, hepatic encephalopathy, and a high mortality rate, and it thus poses a serious threat to patient life. The activation of hepatic stellate cells is a central driver of disease progression. Cellular autophagy, a lysosome-mediated degradation process, plays a key role in maintaining cellular function and dynamic homeostasis. Research has shown that autophagy is closely associated with proteins like LC3, Beclin-1, P62, and mTOR, and is regulated through signaling pathways such as PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR. Additionally, the relationship between autophagy and apoptosis, as well as between autophagy and exosomes, has been further demonstrated. While modern medicine has made progress in treating cirrhosis, it still faces significant limitations. By contrast, numerous studies have demonstrated the efficacy of traditional Chinese medicine in preventing and treating liver cirrhosis by regulating autophagy, with fewer adverse effects. Chinese herbal monomers and formulations can modulate various autophagy-related signaling pathways, including PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, and AMPK/mTOR, and influence key autophagy proteins such as LC3 and Beclin-1. This modulation inhibits hepatic stellate cell activation, reduces extracellular matrix deposition, and exerts anticirrhotic effects. Moreover, Chinese medicine appears to reduce adverse reactions in cirrhosis treatment and lower the risk of disease recurrence. This review explores the mechanisms of autophagy in the prevention and treatment of liver cirrhosis through Chinese medicine, offering new insights for the development of Chinese medicinal therapies for cirrhosis and their rational clinical application.
It is widely acknowledged that there is a considerable number of oncogenic mutations within the Ras superfamily of small GTPases which are the driving force behind a multitude of cancers. Ras proteins mediate a plethora of kinase pathways, including the MAPK, PI3K, and Ral pathways. Since Ras was considered undruggable until recently, pharmacological targeting of pathways downstream of Ras has been attempted to varying success, though drug resistance has often proven an issue. Nuances between kinase pathway activation in the presence of various Ras mutants are thought to contribute to the resistance, however, the reasoning behind activation of different pathways in different Ras mutational contexts is yet to be fully elucidated. Indeed, such disparities often depend on cancer type and disease progression. However, we are in a revolutionary age of Ras mutant targeted therapy, with direct-targeting KRAS-G12C inhibitors revolutionising the field and achieving FDA-approval in recent years. However, these are only beneficial in a subset of patients. Approximately 90% of Ras-mutant cancers are not KRAS-G12C mutant, and therefore raises the question as to whether other distinct amino acid substitutions within Ras may one day be targetable in a similar manner, and indeed whether better understanding of the downstream pathways these various mutants activate could further improve therapy. Here, we discuss the favouring of kinase pathways across an array of Ras-mutant oncogenic contexts and assess recent advances in pharmacological targeting of various Ras mutants. Ultimately, we will examine the utility of individualised pharmacological approaches to Ras-mediated cancer.
Introduction:
Molecular Dynamics (MD) simulations can support mechanism-based drug design. Indeed, MD simulations by capturing biomolecule motions at finite temperatures can reveal hidden binding sites, accurately predict drug-binding poses, and estimate the thermodynamics and kinetics, crucial information for drug discovery campaigns. Small-Guanosine Triphosphate Phosphohydrolases (GTPases) regulate a cascade of signaling events, that affect most cellular processes. Their deregulation is linked to several diseases, making them appealing drug targets. The broad roles of small-GTPases in cellular processes and the recent approval of a covalent KRas inhibitor as an anticancer agent renewed the interest in targeting small-GTPase with small molecules.
Area covered:
This review emphasizes the role of MD simulations in elucidating small-GTPase mechanisms, assessing the impact of cancer-related variants, and discovering novel inhibitors.
Expert opinion:
The application of MD simulations to small-GTPases exemplifies the role of MD simulations in the structure-based drug design process for challenging biomolecular targets. Furthermore, AI and machine learning-enhanced MD simulations, coupled with the upcoming power of quantum computing, are promising instruments to target elusive small-GTPases mutations and splice variants. This powerful synergy will aid in developing innovative therapeutic strategies associated to small-GTPases deregulation, which could potentially be used for personalized therapies and in a tissue-agnostic manner to treat tumors with mutations in small-GTPases.
