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The role of MET receptor tyrosine kinase in non-small cell lung cancer and clinical development of targeted anti-MET agents.

ABSTRACT: A better understanding of the pathophysiology and evolution of non-small cell lung cancer (NSCLC) has identified a number of molecular targets and spurred development of novel targeted therapeutic agents. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of human cancers, including NSCLC. Amplification of MET has been reported in approximately 5%-22% of lung tumors with acquired resistance to small-molecule inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR inhibitors is likely mediated through downstream activation of the phosphoinositide 3-kinase /AKT pathway. Simultaneous treatment of resistant tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of downstream effectors of cell growth, proliferation, and survival, thereby overcoming acquired resistance to EGFR inhibitors. Development and preclinical testing of multiple agents targeting the HGF-MET pathway, including monoclonal antibodies targeting HGF or the MET receptor and small-molecule inhibitors of the MET tyrosine kinase, have confirmed the crucial role of this pathway in NSCLC. Several agents are now in phase III clinical development for the treatment of NSCLC. This review summarizes the role of MET in the pathophysiology of NSCLC and in acquired resistance to EGFR inhibitors and provides an update on progress in the clinical development of inhibitors of MET for treatment of NSCLC.

SUBMITTER: Robinson KW

PROVIDER: S-EPMC3579594 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies.MethodsEighty-six NSCLC patients were categorized into three cohorts based on the time of detecting MET tyrosine kinase domain (TKD) mutations (cohort 1: at baseline; cohort 2: after MET-TKI treatment; cohort 3: after EGFR-TKI treatment). Baseline and paired TKI treatment samples were analyzed by targeted next-generation sequencing.ResultsMET TKD mutations were highly prevalent in METex14-positive NSCLC patients after MET-TKI treatment, including L1195V, D1228N/H/Y/E, Y1230C/H/N/S, and a double-mutant within codons D1228 and M1229. Missense mutations in MET TKD were also identified at baseline and in post-EGFR-TKI treatment samples, which showed different distribution patterns than those in post-MET-TKI treatment samples. Remarkably, H1094Y and L1195F, absent from MET-TKI-treated patients, were the predominant type of MET TKD mutations in patients after EGFR-TKI treatment. D1228H, which was not found in treatment-naïve patients, also accounted for 14.3% of all MET TKD mutations in EGFR-TKI-treated samples. Two patients with baseline EGFR-sensitizing mutations who acquired MET-V1092I or MET-H1094Y after first-line EGFR-TKI treatment experienced an overall improvement in their clinical symptoms, followed by targeted therapy with MET-TKIs.ConclusionsMET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

Project description:Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3–7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Project description:Historical, the non-small cell lung cancer (NSCLC) was as a united disease entity and the chemotherapy to the metastatic cancer had limited results. Recent studies for the metastatic non-small cell lung cancer led to the ascertainment that the NSCLC does not constitute exclusively a disease entity, but different neoplasms guided from different molecular paths, different biological behavior and at extension requires different confrontation. Thus the new direction for the therapeutic approach of NSCLC is henceforth the most individualized approach based on the activated molecular paths of tumor. Distinct subtypes of NSCLC are driven by a specific genetic alteration, like EGFR, ALK, ROS1 or BRAF mutations, and these genetic alterations are sensitized to the inhibition of specific oncogenic pathways. The benefit from the use of tyrosine kinase inhibitors in patients with EGFR mutations it was confirmed by six randomized studies of phase III that investigated the role of gefitinib, erlotinib and afatinib. In these studies the response rates vary in the impressive percentages from 55% to 86% and were connected with a remarkable median progression free survival of approximately 8 to 13 months, and with better quality of life compared to that of chemotherapy. In early stages NSCLC is needed the individualization of systemic treatment in order to reduce toxicity that is observed in the classic chemotherapy and to impact outcome. The role of EGFR TKI's has been evaluated in the adjuvant chemotherapy in early stage resected NSCLC. The data from these studies suggest that adjuvant TKI therapy might not increase the overall survival, but delay the recurrences. Prospective trials restricted to EGFR or ALK driven NSCLC subsets potentially offering the opportunity for a definitive answer in early disease adjuvant setting (ALCHEMIST) or as induction treatment before stage III chemo-radiotherapy (RTOG 1210/Alliance 31101), are ongoing. Ongoing prospective trials may offer the opportunity for a definitive answer of the role of tyrosine kinase inhibitors in induction treatment before chemo-radiotherapy or in early disease adjuvant therapy.

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The role of MET receptor tyrosine kinase in non-small cell lung cancer and clinical development of targeted anti-MET agents.

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