Reference Detail

Ref Type Journal Article
PMID (28765324)
Authors Engstrom L, Aranda R, Lee M, Tovar EA, Essenburg C, Madaj ZB, Chiang H, Briere D, Hallin J, Lopez-Casas PP, Banos N, Menéndez C, Hidalgo M, Tassell V, Chao R, Chudova DI, Lanman RB, Olson P, Bazhenova L, Patel SP, Graveel CR, Nishino M, Shapiro GI, Peled N, Awad MM, Janne PA, Christensen JG
Title 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.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol
Issue
Date 2017 Aug 01
URL
Abstract Text 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 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET Inhibitors.<br /><br />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.<br /><br />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 mutation-positive 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. <br /><br />Conclusions: Together, these data demonstrate glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

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
F1200L missense unknown MET F1200L lies within the protein kinase domain of the Met protein (UniProt.org). F1200L has been described as a secondary drug resistance mutation (PMID: 28765324), but has not been biochemically characterized and therefore, its effect on Met protein function is unknown (PubMed, Feb 2019). Y
G1163R missense unknown MET G1163R lies within the protein kinase domain of the Met protein (UniProt.org). G1163R has been described as a secondary drug resistance mutation due to its inability to bind some Met inhibitors (PMID: 21697284, PMID: 28765324), 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
MET Y1230C Advanced Solid Tumor sensitive Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, a transformed cell line expressing MET Y1230C was sensitive to Glesatinib (MGCD265), demonstrating inhibition of cell growth in culture and 88% tumor regression in xenograft models (PMID: 28765324). 28765324
MET del exon14 lung adenocarcinoma predicted - sensitive Glesatinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring a MET exon 14 skipping mutation demonstrated a 66% reduction in target lesion size and maintained a partial response for 7 months when treated with Glesatinib (MGCD265) (PMID: 28765324). 28765324
MET amp lung cancer sensitive Glesatinib Preclinical - Cell culture Actionable In a preclinical study, Glesatinib (MGCD265) inhibited Met phosphorylation and growth of MET-amplified lung cancer cells in culture (PMID: 28765324). 28765324
MET Y1230C stomach cancer resistant Capmatinib Preclinical - Cell culture Actionable In a preclinical study, a gastric adenocarcinoma cell line (PMID: 15494073) treated with Capmatinib (INC280) in culture for several months developed resistance and was found to harbor MET Y1230C (PMID: 28765324). 15494073 28765324
MET del exon14 Advanced Solid Tumor sensitive Capmatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing a deletion of MET exon 14 were sensitive to Capmatinib (INC280) treatment in culture, demonstrating inhibition of spheroid growth (PMID: 28765324). 28765324
MET amp MET del exon14 non-small cell lung carcinoma sensitive Glesatinib Preclinical - Pdx Actionable In a preclinical study, Glesatinib (MGCD265) treatment resulted in tumor regression in patient-derived xenograft (PDX) models of non-small cell lung cancer harboring deletion of MET exon 14 and varying degrees of MET amplification (PMID: 28765324). 28765324
MET amp stomach cancer sensitive Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) treatment resulted in tumor regression in MET-amplified gastric cancer cell line xenograft models (PMID: 28765324). 28765324
MET wild-type Advanced Solid Tumor decreased response Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) treatment resulted in only partial growth inhibition in MET wild-type cell line xenograft models of various tumor types (PMID: 28765324). 28765324
MET amp MET del exon14 MET D1228N MET G1163R MET Y1230H MET Y1230S lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a lung adenocarcinoma patient harboring MET deletion exon 14 and MET amplification demonstrated resistance to Xalkori (crizotinib), and the patient was found to have acquired MET Y1230H, MET D1228N, MET Y1230S, and MET G1163R (PMID: 28765324). 28765324
MET del exon14 lung cancer sensitive Glesatinib Preclinical - Cell culture Actionable In a preclinical study, Glesatinib (MGCD265) inhibited Met phosphorylation and growth in lung cancer cells harboring a deletion of MET exon 14 and loss of the wild-type MET allele in culture (PMID: 28765324). 28765324
MET wild-type colorectal cancer decreased response Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) treatment resulted in only partial growth inhibition in cell line xenograft models of MET wild-type colorectal cancer (PMID: 28765324). 28765324
MET amp MET del exon14 MET D1228N MET G1163R MET L1195V lung adenocarcinoma predicted - resistant Glesatinib Case Reports/Case Series Actionable In a clinical case study, a lung adenocarcinoma patient previously harboring MET amp, MET deletion exon 14, MET D1228N, MET Y1230H, MET Y1230S, and MET G1163R demonstrated a decrease in lesion size when treated with Glesatinib (MGCD265), however, progression ensued and plasma testing indicated the patient lost Y1230H and Y1230S, but acquired MET L1195V (PMID: 28765324). 28765324
MET del exon14 Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing a deletion of MET exon 14 were sensitive to Xalkori (crizotinib) treatment in culture, demonstrating inhibition of spheroid growth (PMID: 28765324). 28765324
MET F1200L MET Y1230H stomach cancer resistant Capmatinib Preclinical - Cell culture Actionable In a preclinical study, a gastric adenocarcinoma cell line (PMID: 15494073) co-harboring MET Y1230H and MET F1200L demonstrated resistance when treated with Capmatinib (INC280) in culture (PMID: 28765324). 28765324 15494073
MET del exon14 MET D1228N Advanced Solid Tumor sensitive Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells expressing MET deletion exon 14 and MET D1228N were sensitive to Glesatinib (MGCD265) treatment, demonstrating cell growth inhibition in culture and 21% tumor regression in xenograft models (PMID: 28765324). 28765324
MET del exon14 MET Y1230C Advanced Solid Tumor sensitive Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells expressing MET deletion exon 14 and MET Y1230C were sensitive to Glesatinib (MGCD265) treatment, demonstrating cell growth inhibition in culture and 52% tumor regression in xenograft models (PMID: 28765324). 28765324
MET wild-type breast cancer decreased response Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) treatment only resulted in partial growth inhibition in cell line xenograft models of MET wild-type breast cancer (PMID: 28765324). 28765324
MET F1200L MET Y1230H stomach cancer sensitive Glesatinib Preclinical - Cell culture Actionable In a preclinical study, a gastric adenocarcinoma cell line (PMID: 15494073) co-harboring MET Y1230H and MET F1200L was sensitive to treatment with Glesatinib (MGCD265), demonstrating cell growth inhibition in culture (PMID: 28765324). 28765324 15494073
MET del exon14 Advanced Solid Tumor sensitive Glesatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing deletion of MET exon 14 were sensitive to Glesatinib (MGCD265) treatment in culture, demonstrating inhibition of spheroid growth (PMID: 28765324). 28765324
MET wild-type pancreatic cancer decreased response Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) treatment resulted in only partial growth inhibition in cell line xenograft models of MET wild-type pancreatic cancer (PMID: 28765324). 28765324
MET del exon14 stomach cancer sensitive Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) inhibited Met phosphorylation and growth in gastric cancer cells harboring a deletion of MET exon 14 and amplification of the mutant allele in culture, and resulted in tumor regression in cell line xenograft models (PMID: 28765324). 28765324
MET Y1230C stomach cancer sensitive Glesatinib Preclinical - Cell culture Actionable In a preclinical study, a gastric adenocarcinoma cell line (PMID: 15494073) harboring MET Y1230C was sensitive to treatment with Glesatinib (MGCD265), demonstrating cell growth inhibition in culture (PMID: 28765324). 28765324 15494073
MET wild-type prostate cancer decreased response Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) treatment resulted in only partial growth inhibition in cell line xenograft models of MET wild-type prostate caner (PMID: 28765324). 28765324
MET Y1230C stomach cancer resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, a Capmatinib (INC280)-resistant gastric cancer cell line (PMID: 15494073) harboring MET Y1230C also demonstrated resistance when treated with Xalkori (crizotinib) (PMID: 28765324). 15494073 28765324
MET wild-type bladder carcinoma decreased response Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Glesatinib (MGCD265) treatment resulted in only partial growth inhibition in cell line xenograft models of MET wild-type urinary bladder carcinoma (PMID: 28765324). 28765324
MET amp MET del exon14 lung cancer sensitive Glesatinib Preclinical - Pdx Actionable In a preclinical study, a lung cancer patient-derived xenograft (PDX) model harboring MET amplification and MET exon 14 deletion demonstrated tumor regression when treated with Glesatinib (MGCD265) (PMID: 28765324). 28765324
MET amp MET del exon14 lung adenocarcinoma predicted - sensitive Crizotinib Case Reports/Case Series Actionable In a clinical case study, a lung adenocarcinoma patient co-harboring MET exon 14 deletion and MET amp was sensitive to Xalkori (crizotinib), demonstrating a partial response for 8 months (PMID: 28765324). 28765324
MET F1200L MET Y1230H stomach cancer resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, a gastric adenocarcinoma cell line (PMID: 15494073) treated with Xalkori (crizotinib) in culture for several months developed resistance and was found to co-harbor MET Y1230H and MET F1200L(PMID: 28765324). 28765324 15494073