Audrey Vinchent

Receptor tyrosine kinases (RTK) classically function as oncogenic drivers that promote survival and proliferation upon ligand binding. A subset of RTKs can also function as dependence receptors (DR), inducing apoptosis in the absence of their ligands. Genetic alterations that enhance RTK signaling are well characterized in cancer and can be targeted with kinase inhibitors, which show limited efficacy in some clinical settings. Elucidation of whether oncogenic mutations can promote tumorigenesis by directly abolishing the proapoptotic activity of DRs could help improve strategies to target RTKs. In this study, we identified MET exon 14 skipping (METex14Del) as a paradigmatic example of an oncogenic alteration that drives tumorigenesis through genetic inactivation of the DR function of an RTK. METex14Del removed both the caspase cleavage site and adjacent Casitas B-lineage lymphoma (CBL)-binding motif, preventing generation of the proapoptotic p40MET fragment while sustaining oncogenic MET signaling. Uncoupling regulatory functions of MET using genome editing showed that loss of apoptosis capacity is a critical determinant of METex14Del-driven tumorigenesis. Combined—but not individual—mutation of the caspase and CBL sites was sufficient to recapitulate resistance to apoptosis and tumor growth induced by METex14Del in hepatocyte growth factor–humanized mouse models. Importantly, inducible reexpression of p40MET in METex14Del-expressing cells restored apoptotic sensitivity, decreased tumor formation in vivo, and resensitized tumors to capmatinib. Together, these findings redefine RTKs as receptors with dual oncogenic and tumor-suppressive functions and show that disruption of DR-mediated apoptosis is an oncogenic mechanism. These results provide a conceptual framework explaining why therapies targeting only RTK signaling may fail and support strategies restoring DR function to achieve durable tumor suppression. Significance: MET exon 14 skipping drives tumorigenesis not only by sustaining signaling but by genetically disabling the dependence receptor–mediated apoptotic function of MET, uncovering a mechanism explaining resistance to kinase-targeted therapies.