[Show abstract][Hide abstract] ABSTRACT: Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9–13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer.
The Lancet Oncology 12/2014; 15(13):1433-41. DOI:10.1016/S1470-2045(14)70461-9 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Patients with stage III non-small-cell lung cancer and poor performance status and/or weight loss do not seem to benefit from standard therapy. Based on the preclinical interaction between epidermal growth factor receptor inhibitors and radiation, we designed a trial of induction chemotherapy followed by thoracic radiotherapy and concurrent erlotinib.
Patients with poor-risk unresectable stage III non-small-cell lung cancer received two cycles of carboplatin at an AUC of 5 and nab-paclitaxel at 100 mg/m on days 1 and 8 every 21 days, followed by erlotinib administered concurrently with thoracic radiotherapy. Maintenance was not permitted. Molecular analysis was performed in available specimens. Seventy-two eligible patients were required to test whether the 1-year survival rate was less than 50% or greater than or equal to 65% with approximately 90% power at a significance level of 0.10.
From March 2008 to October 2011, 78 patients were enrolled, three of whom were ineligible. The median age was 68 (range, 39-88) and 32% were aged greater than or equal to 75 years. Patients were evenly distributed between stages IIIA and IIIB and the majority had performance status 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the prespecified target for significance.
Patients with poor-risk stage III non-small-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2014; 10(1). DOI:10.1097/JTO.0000000000000347 · 5.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
Proceedings of the National Academy of Sciences 10/2014; 111(45). DOI:10.1073/pnas.1403438111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.
Nature Chemical Biology 10/2014; 10(12). DOI:10.1038/nchembio.1658 · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.
New England Journal of Medicine 10/2014; 371(15):1426-1433. DOI:10.1056/NEJMoa1403352 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The discovery of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has allowed the identification of a subset of patients whose tumours are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). Despite the efficacy and superiority of EGFR TKIs over chemotherapy as first-line therapy, all patients will ultimately develop progressive disease, with a median of 9-13 months progression-free survival. A better understanding of the molecular mechanisms underlying resistance to EGFR TKIs can help design new drugs and therapeutic strategies to overcome resistance. This has been illustrated by the new generation TKIs that are effective on the T790M mutation, which is the most frequent mechanism of acquired resistance to EGFR TKIs. In this article, we will address the main molecular mechanisms of primary and acquired resistance to EGFR TKIs in EGFR-mutant NSCLC.
European Respiratory Review 09/2014; 23(133):356-66. DOI:10.1183/09059180.00004614
[Show abstract][Hide abstract] ABSTRACT: MET targeted therapies are under clinical evaluation for non-small-cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKI) against MET have varying degrees of specificity. Tivantinib (ARQ 197) is reported to be a non-ATP competitive selective MET inhibitor. We aimed to compare the activity of tivantinib to other MET TKIs in a panel of NSCLC cell lines classified by their MET dependency and characterized by different relevant genotypes. A549, H3122, PC9 and HCC827, their respective resistant clones PC9 GR4 and HCC827 GR6 and the MET amplified cell lines H1993 and EBC-1 were treated in vitro with tivantinib, crizotinib or PHA-665752. Crizotinib and PHA-665752 showed growth inhibition restricted to MET dependent cell lines. The pattern of activity was related to MET inhibition and downstream signaling inhibition of AKT and ERK1/2, inducing G0/G1 cycle arrest and apoptosis. In contrast to crizotinib and PHA-665752, tivantinib possessed more potent anti-proliferative activity that was not restricted to only MET dependent cell lines. Tivantinib did not inhibit cellular MET activity nor inhibit phosphorylation of downstream effects such as AKT or ERK1/2 in either MET dependent or independent cell lines. Cell cycle analysis demonstrated that tivantinib induced a G2/M arrest and induced apoptosis. Tivantinib but not crizotinib effected microtubule dynamics, disrupting mitotic spindles by a mechanism consistent with it functioning as a microtubule depolymerizer. Tivantinib activity is independent of MET signaling in NSCLC and suggests alternative mechanisms of action that should be considered when interpreting the results from on-going clinical studies.
[Show abstract][Hide abstract] ABSTRACT: Objectives
The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined.
Materials and methods
A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990-2012.
300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stage I-III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4-32), compared to 3 (1%) patients with typical carcinoid (range, 8-12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum-etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5 year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 m median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 m median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6-72 months).
These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy.
Lung Cancer 08/2014; 86(2). DOI:10.1016/j.lungcan.2014.08.012 · 3.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor biopsies remain the gold standard for the evaluation of genetic changes in tumors either at diagnosis or after treatment with targeted therapies. However, this is not always feasible and can seldom be performed more than once. Noninvasive techniques that measure the allelic burden in blood have the potential to realize genotype‐directed cancer therapy. These technologies can potentially be used for noninvasive tumor genotyping and also provide an opportunity for disease monitoring. Several non‐invasive genotyping technologies are currently under development and being evaluated in patients treated with targeted therapies.
Cancer 08/2014; 120(24). DOI:10.1002/cncr.28967 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers.