Reference Detail

Ref Type Journal Article
PMID (27694386)
Authors Bahcall M, Sim T, Paweletz CP, Patel JD, Alden RS, Kuang Y, Sacher AG, Kim ND, Lydon CA, Awad MM, Jaklitsch MT, Sholl LM, Jänne PA, Oxnard GR
Title Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer.
Journal Cancer discovery
Vol 6
Issue 12
Date 2016 Dec
URL
Abstract Text Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET(D1228V) induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response.With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired MET(D1228V) mutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. Cancer Discov; 6(12); 1334-41. ©2016 AACR.See related commentary by Trusolino, p. 1306This article is highlighted in the In This Issue feature, p. 1293.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D1228V missense unknown MET D1228V lies within the protein kinase domain of the Met protein (UniProt.org). D1228V has been described as a secondary drug resistance mutation due to its inability to bind some Met inhibitors (PMID: 27694386), but has not been biochemically characterized and therefore, its effect on Met protein function is unknown (PubMed, Feb 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EGFR exon 19 del MET amp MET D1228V lung adenocarcinoma predicted - resistant Osimertinib + Savolitinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring an EGFR exon 19 deletion and MET amplification demonstrated a near complete response when treated with the combination of Savolitinib (AZD6094) and Tagrisso (osimertinib) obtained through a Phase I trial, however, after 36 weeks presented with progression and MET D1228V was identified as an acquired mutation (PMID: 27694386; NCT02143466). 27694386
MET D1228V Advanced Solid Tumor sensitive Merestinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing MET D1228V were sensitive to Merestinib (LY2801653) in culture, resulting in suppression of Met phosphorylation (PMID: 27694386). 27694386
MET D1228V Advanced Solid Tumor resistant Capmatinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing MET D1228V demonstrated resistance to treatment with Capmatinib (INC280) in culture, resulting in sustained Met phosphorylation (PMID: 27694386). 27694386
EGFR exon 19 del MET amp MET D1228V lung adenocarcinoma predicted - sensitive Cabozantinib + Erlotinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring an EGFR exon 19 deletion, MET amplification, and MET D1228V demonstrated a strong response to the combination of Tarceva (erlotinib) and Cometriq (Cabometyx, cabozantinib), resulting in reduced tumor size and continued clinical benefit 5 months after the start of therapy (PMID: 27694386). 27694386
MET D1228V Advanced Solid Tumor sensitive Cabozantinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing MET D1228V were sensitive to Cometriq (Cabometyx, cabozantinib) in culture, resulting in suppression of Met phosphorylation (PMID: 27694386). 27694386
EGFR exon 19 del MET amp lung adenocarcinoma predicted - sensitive Osimertinib + Savolitinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring an EGFR exon 19 deletion and MET amplification demonstrated a near complete response when treated with the combination of Savolitinib (AZD6094) and Tagrisso (osimertinib) obtained through a Phase I trial, however, after 36 weeks presented with progression (PMID: 27694386; NCT02143466). 27694386
EGFR exon 19 del MET amp lung adenocarcinoma resistant Erlotinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring an EGFR exon 19 deletion and MET amplification was resistant to Tarceva (erlotinib) (PMID: 27694386). 27694386
MET D1228V Advanced Solid Tumor sensitive Glesatinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing MET D1228V were sensitive to Glesatinib (MGCD265) in culture, resulting in suppression of Met phosphorylation (PMID: 27694386). 27694386
EGFR exon 19 del MET amp lung adenocarcinoma predicted - resistant Afatinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring an EGFR exon 19 deletion and MET amplification was resistant to Gilotrif (afatinib) (PMID: 27694386). 27694386
MET D1228V Advanced Solid Tumor resistant Savolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing MET D1228V demonstrated resistance to treatment with Savolitinib (AZD6094) in culture, resulting in sustained Met phosphorylation (PMID: 27694386). 27694386
MET D1228V Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing MET D1228V demonstrated resistance to treatment with Xalkori (crizotinib) in culture, resulting in sustained Met phosphorylation (PMID: 27694386). 27694386