Functional Analysis of MET Exon 14 Skipping Alteration in Cancer Invasion and Metastatic Dissemination

MET exon 14 skipping alteration (MET Delta 14Ex) is an actionable oncogenic driver that occurs in 2% to 4% of non-small cell lung cancer (NSCLC) cases. The precise role of MET Delta 14Ex in tumor progression of NSCLC is poorly understood. Using multiple isogenic MET Delta 14Ex cell models established with CRISPR editing, we demonstrate that MET Delta 14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, significantly boosting cell scatter, migration, and invasion capacity in vitro as well as metastasis in vivo. RNA sequencing analysis revealed that MET Delta 14Ex preferentially activates biological processes associated with cell movement, providing novel insights into its unique molecular mechanism of action. Activation of PI3K/Akt/Rac1 signaling and upregulation of multiple matrix metallopeptidases (MMP) by MET Delta 14Ex induced cytoskeleton remodeling and extracellular matrix disassembly, which are critical functional pathways that facilitate cell invasion and metastasis. Therapeutically, MET inhibitors dramatically repressed MET Delta 14Ex-mediated tumor growth and metastasis in vivo, indicating potential therapeutic options for MET Delta 14Ex-altered NSCLC patients. These mechanistic insights into MET Delta 14Ex-mediated invasion and metastasis provide a deeper understanding of the role of MET Delta 14Ex in NSCLC. Significance: These findings reveal the mechanistic function of MET Delta 14Ex alteration in driving metastasis and define novel metastasis-related pathways that could be targeted for more effective treatment of lung cancer with MET Delta 14Ex alterations.