Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than those for targeted TKIs of other oncogene-addicted NSCLCs. Given the known interplay between MET and phosphoinositide 3-kinases (PI3K), we hypothesized that in METex14 NSCLC, PI3K pathway alterations might contribute to primary resistance to MET TKIs. We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K pathway alterations by targeted next-generation sequencing (mutations) and immunohistochemistry (loss of phosphatase and tensin homolog [PTEN]). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both a METex14 mutation and a PI3K pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. We found a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutation in two of 65 samples (3%) and loss of PTEN in six of 26 samples (23%). All three of the MET TKI–treated patients with a PI3K pathway alteration had been found to have progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation of METex14-mutated cell lines with a PI3K pathway alteration, including the PTEN-lacking patient-derived cell line. Treatment combining a MET TKI with a PI3K inhibitor caused inhibition of both PI3K and MAPK signaling and restored sensitivity to MET TKIs. PI3K pathway alterations are common in METex14 NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs.
Keywords
TKI
Resistance
MET
PI3K
NSCLC
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Disclosure: Pr. Cortot participated in advisory boards or received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck & Co., Pfizer, Roche, Novartis, and Takeda, and received grants paid to his institution from Novartis and Merck. Dr. Jamme reports nonfinancial support from Chugai Pharma, Roche, and Bristol-Myers Squibb, and personal fees from Boehringer Ingelheim, outside of the submitted work. Dr. Baldacci reports personal fees and nonfinancial support from Lilly, GlaxoSmithKline, Roche, Pfizer, and a grant from the Intergroupe Francophone de Cancérologie Thoracique, outside of the submitted work. Pr. Copin participates in advisory boards for Pfizer and Roche. Dr. Descarpentries reports personal fees and nonfinancial support from AstraZeneca, Novartis Pharma S.A.S., Roche S.A.S., Boehringer Ingelheim France, and Pfizer, outside of the submitted work. The remaining authors declare no conflict of interest.
