Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).

Awad, Mark M.; Bahcall, Magda; Sholl, Lynette M.; Wilson, Frederick H.; Paweletz, Cloud P.; Capelletti, Marzia; Leonardi, Giulia C.; Watanabe, Masayuki; Baba, Hideo; Chambers, Emily S.; Redig, Amanda J.; Nishino, Mizuki; VanderLaan, Paul A.; Costa, Daniel B.; Imamura, Yu

doi:10.1200/jco.2018.36.15_suppl.9069

Cited by 9 publications

(7 citation statements)

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“…Taken together, these findings suggest that mechanisms of resistance to different MET inhibitors are complex and diverse, and may vary due to differing mechanisms of action of MET inhibitors [41]. Clearly, novel therapeutic strategies will be needed to combat multiple complex resistance mechanisms [81], possibly in the form of sequencing or combination approaches [77,83].…”

Section: Tablementioning

confidence: 96%

“…However, several resistance mechanisms have been reported, including additional mutations in MET exon 14 [79,80], upregulation of bypass signaling pathways, and/or the acquisition of additional oncogenic mutations. A study of mechanisms of resistance to the MET TKIs crizotinib and glesatinib reported acquired mutated MET exon 14 allele amplification or MET tyrosine kinase domain secondary site mutations and bypass track activation, including amplification of wild-type KRAS, BRAF, and/or EGFR [81]. Interestingly, the same study showed that one patient who acquired resistance to glesatinib through mutated MET exon 14 allele amplification reported a confirmed partial response after switching to crizotinib [81].…”

Section: Tablementioning

confidence: 99%

“…A study of mechanisms of resistance to the MET TKIs crizotinib and glesatinib reported acquired mutated MET exon 14 allele amplification or MET tyrosine kinase domain secondary site mutations and bypass track activation, including amplification of wild-type KRAS, BRAF, and/or EGFR [81]. Interestingly, the same study showed that one patient who acquired resistance to glesatinib through mutated MET exon 14 allele amplification reported a confirmed partial response after switching to crizotinib [81]. Another study of paired tumor biopsies reported resistance acquired via additional MET pathway alterations or via activation of other pathways, including EGFR and RAS [82].…”

Section: Tablementioning

confidence: 99%

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The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

Salgia

Sattler

Scheele

et al. 2020

Cancer Treatment Reviews

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Dysregulated activation of the MET tyrosine kinase receptor is implicated in the development of solid tumors and can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor (HGF), and the acquisition of activating mutations. The most common activating mutations cause exon 14 to be skipped during MET mRNA splicing. This in-frame deletion, known as MET exon 14, results in production of a shortened receptor that lacks a juxtamembrane domain but retains affinity for HGF. However, the negative regulatory function located within this protein sequence is lost, leading to receptor accumulation on the cell surface and prolonged activation by HGF. MET mutations causing exon 14 skipping appear to be true oncogenic drivers and occur in patients and tumors with distinct characteristics.Increasing evidence suggests that tumors carrying such mutations are sensitive to MET inhibition, raising the hope that selective MET inhibitors will provide patients with optimal anticancer activity with minimal toxicity.We discuss the prospects for selective MET inhibitors in the treatment of non-small cell lung cancer harboring MET exon 14 skipping.

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Section: Tablementioning

confidence: 96%

Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

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The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

Salgia

Sattler

Scheele

et al. 2020

Cancer Treatment Reviews

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“…Several studies in MET inhibitor-treated MET ex14-positive NSCLC have similarly reported various types of secondary MET mutations, including those at D1228 and Y1230 residues, that were acquired upon disease progression. 6 , 24 – 27 Mutations involving D1228 and Y1230 residues in the activation loop prevent the binding of type I MET inhibitors, including savolitinib, leading to resistance that can potentially be circumvented by type II MET inhibitors (e.g. cabozantinib, glesatinib and merestinib), supporting the sequential use of type I and II MET inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Available evidence similarly showed that RAS/RAF/mitogen-activated protein kinase pathway alterations at baseline and upon disease progression were implicated with primary and acquired resistance to other MET inhibitors, respectively, in patients with MET ex14-positive NSCLC. 24 – 26 , 31 The inhibition of Src homology 2 domain-containing-phosphatase 2, a common RAS upstream signalling node of multiple oncogenic pathways, was shown to delay and overcome tepotinib resistance in cell lines. 32 In the present study, we also observed acquired gene alterations in other components of the RTK-RAS-PI3K pathway, as well as those involved in DNA damage response, and transcriptional and epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

Circulating tumour DNA biomarkers in savolitinib-treated patients with non-small cell lung cancer harbouringMETexon 14 skipping alterations: apost hocanalysis of a pivotal phase 2 study

et al. 2022

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Background: Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouring MET exon 14 skipping alteration ( METex14). Objective: To analyse post hoc, the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib. Design: A multicentre, single-arm, open-label phase 2 study. Methods: All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baseline METex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression. Results: Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable METex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline METex14 exhibited worse PFS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 0.88–3.57; p = 0.108] and OS (HR, 3.26; 95% CI, 1.35–7.89; p = 0.006) than those without, despite showing a numerically higher ORR. Among 24 patients with baseline detectable METex14 and evaluable postbaseline samples, 13 achieved METex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7–1.5). METex14 post-treatment clearance was associated with better ORR (92.3%; 95% CI, 64.0–99.8 versus 36.4%; 95% CI, 10.9–69.2; p = 0.0078), PFS (HR, 0.44; 95% CI, 0.2–1.3; p = 0.1225) and OS (HR, 0.31; 95% CI, 0.1–1.0; p = 0.0397) versus non-clearance. Among 22 patients with disease progression, 10 acquired pathway alterations (e.g. in RAS/RAF and PI3K/PTEN) alone or with secondary MET mutations (D1228H/N and Y1230C/H/S). Conclusion: ctDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients with METex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. Registration: The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

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Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).

Cited by 9 publications

References 0 publications

The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

Circulating tumour DNA biomarkers in savolitinib-treated patients with non-small cell lung cancer harbouringMETexon 14 skipping alterations: apost hocanalysis of a pivotal phase 2 study

Glesatinib

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