Alterations in the PI3K pathway drive resistance to MET inhibitors in NSCLC harboring MET exon 14 skipping mutations.

Abstract Introduction MET TKIs (tyrosine kinase inhibitors) have demonstrated efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than for targeted TKIs of other oncogene-addicted NSCLC. Given the known interplay between MET and PI3K, we hypothesized that in METex14 NSCLC, PI3K-pathway alterations might contribute to primary resistance to MET TKIs. Methods We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K-pathway alterations by targeted NGS (mutations) and immunohistochemistry (loss of 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. Results We found a PIK3CA mutation in 2/65 samples (3%) and loss of PTEN in 6/26 (23%). All three of the MET-TKI-treated patients with a PI3K pathway alteration had shown 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. Conclusion 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.