Acquired Resistance to Crizotinib in NSCLC with MET  Exon 14 Skipping

Heist, Rebecca S.; Sequist, Lecia V.; Borger, Darrell R.; Gainor, Justin F.; Arellano, Ronald S.; Le, Long P.; Dias‐Santagata, Dora; Clark, Jeffrey W.; Engelman, Jeffrey A.; Shaw, Alice T.; Iafrate, A. John

doi:10.1016/j.jtho.2016.06.013

Cited by 136 publications

(105 citation statements)

References 15 publications

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“…Our observations of mutations at D1228, Y1230, and F1200 either linked to intrinsic resistance or following long-term drug exposure to type I MET inhibitors are consistent with previous studies. Multiple clinical case reports implicating D1228 and Y1230 mutations in resistance to crizotinib have emerged recently indicating that these mutations have clinical relevance (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

“…However, the understanding of resistance mechanisms, including active site mutations and activation of bypass pathways, has resulted in next-generation inhibitors and development of combinatorial treatment strategies to simultaneously target primary and bypass pathways (14)(15)(16)(17). Multiple recent reports of acquired active site resistance mutations in MET following durable clinical responses to crizotinib therapy indicate that targeting MET is not an exception (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…Both glesatinib binding modes are distinct from type I inhibitors and independent of interactions with the A-loop (22,23). MET mutations involving the A-loop residues D1228 and Y1230 that confer resistance to type I MET inhibitors have now been described in model systems and multiple patients (18)(19)(20). Because of the differential engagement of the A-loop, type I and type II MET inhibitors are predicted to be differentially susceptible to certain active site mutations implicated in drug resistance (19,(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

“…MET mutations involving the A-loop residues D1228 and Y1230 that confer resistance to type I MET inhibitors have now been described in model systems and multiple patients (18)(19)(20). Because of the differential engagement of the A-loop, type I and type II MET inhibitors are predicted to be differentially susceptible to certain active site mutations implicated in drug resistance (19,(24)(25)(26). Thus, type II inhibitors are predicted to be effective against certain MET mutations implicated in resistance to type I inhibitors enabling a sequential treatment strategy in the setting of target-mediated drug resistance.…”

Section: Introductionmentioning

confidence: 99%

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Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Engstrom

Aranda

Lee

et al. 2017

Clinical Cancer Research

115

133

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Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 delpositive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutationpositive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661-72. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Engstrom

Aranda

Lee

et al. 2017

Clinical Cancer Research

115

133

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“…When resistance developed to combined MET and EGFR inhibition, a MET D1228V kinase domain mutation was detected. In a separate study, a NSCLC patient with a METex14 deletion was treated with the MET inhibitor crizotinib and upon progression a D1228N mutation was detected (42). Likewise in NSCLC patient with a METex14 deletion, a Y1230C mutation was also detected at a very low frequency (mutant allele frequency =0.3%); however after 13 months of crizotinib treatment the tumor progressed and the Y1230C allele was detected in 3.5% of circulating tumor DNA (43).…”

Section: Reemergence Of Met Kinase Domain Mutations During Resistancementioning

confidence: 96%

MET in human cancer: germline and somatic mutations

Tovar

Graveel

2017

Ann. Transl. Med.

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Since the initial discovery of missense MET mutations in hereditary papillary renal carcinoma (HPRC), activating MET mutations have been identified in a diverse range of human cancers. MET mutations have been identified in several functional domains including the kinase, juxtamembrane, and Sema domains. Studies of these mutations have been invaluable for our understanding of the tumor initiating activity of MET, receptor tyrosine kinase (RTK) recycling and regulation, and mechanisms of resistance to kinase inhibition. These studies also demonstrate that mutationally activated MET plays a significant role in a wide range of cancers and RTKs can promote tumor progression through diverse mechanisms. This review will cover the various MET mutations that have been identified, their mechanism of action, and the significant role that mutationally-activated MET plays in tumor initiation, progression, and therapeutic resistance.

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The METeoric rise of MET in lung cancer

Friedlaender

Drilon

Banna

et al. 2020

Cancer

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Over the years, there has been a continuous increase in clinically relevant driver mutations in patients with non-small cell lung cancer (NSCLC). Among these, dysregulated activation of the MET tyrosine kinase receptor has gained importance due to the recent development of quite effective treatments. MET dysregulation encompasses a heterogeneous array of alterations leading to the prolonged activation of the cellular MET (c-MET or MET) receptor and downstream proliferation pathways. It can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor, and the acquisition of activating mutations. MET mutations are found in approximately 3% to 5% of patients with NSCLC, mainly adenocarcinoma, and are overrepresented in the sarcomatoid subtype. De novo MET amplifications are found in 1% to 5% of NSCLC cases, also predominantly in adenocarcinoma. In the current review, the authors discussed the biology of MET, how to diagnose clinically relevant alterations, and the rising clinical importance of these alterations in light of the emergence of multiple targeted therapies, both within the context of MET as a driver of resistance and in its own right. Cancer 2020;126:4826-4837.

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Acquired Resistance to Crizotinib in NSCLC with MET Exon 14 Skipping

Abstract: One potential mechanism of acquired resistance to crizotinib in patients with MET exon 14 skipping is through second-site mutations in the MET gene. Understanding mechanisms of resistance will be important in optimizing therapy in these patients.

Cited by 136 publications

References 15 publications

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

MET in human cancer: germline and somatic mutations

The METeoric rise of MET in lung cancer

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