Oncogenic mutations convert MET from a pro-apoptotic tumor suppressor to an oncogenic driver
Dependence receptors can exert both oncogenic and tumor-suppressive activities. In cancers, downregulation of dependence receptors or overexpression of their ligands are well-established mechanisms that drive tumor progression. However, direct genetic alterations abolishing the pro-apoptotic function of dependence receptors have not been documented so far. MET, a receptor tyrosine kinase classically viewed as an oncogene, has also been proposed to act as a dependence receptor through its caspase-mediated cleavage, but whether this property impacts tumorigenesis remained unknown. In [~]3% of lung adenocarcinomas, MET mutations leading to exon 14 skipping (METex14Del) remove both the caspase site and the adjacent CBL-binding motif, thereby preventing generation of the pro-apoptotic p40MET fragment. METex14Del promotes sustained signaling, enhanced invasion, apoptosis resistance, and tumor growth in HGF-humanized mice. Genome editing revealed that combined --but not individual-- mutations of the caspase and CBL sites phenocopy METex14Del. Moreover, inducible re-expression of p40MET in METex14Del-expressing cells restored apoptosis and suppressed tumor formation. Altogether, our findings identify MET exon 14 skipping as the first oncogenic mutation that drives tumorigenesis by abolishing the tumor-suppressive pro-apoptotic function of a dependence receptor, thereby redefining the oncogenic potential of MET.