Activating Point Mutations in the <i>MET</i> Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors
Federica Pecci, Seshiru Nakazawa, Biagio Ricciuti, Guilherme Harada, Jessica Lee, Joao V. Alessi, Adriana Barrichello, Victor R. Vaz, Giuseppe Lamberti, Alessandro Di Federico, Malini Gandhi, Dimitris Gazgalis, William W. Feng, Jie Jiang, Simon Baldacci, Marie-Anaïs Locquet, Felix H. Gottlieb, Monica F. Chen, Elinton Lee, Danielle Haradon, Anna Smokovich, Emma Voligny, Tom Nguyen, Vikas K. Goel, Zachary Zimmerman, Sumandeep Atwal, Xinan Wang, Magda Bahcall, Rebecca S. Heist, Sumaiya Iqbal, Nishant Gandhi, Andrew Elliott, Ari M. Vanderwalde, C. Patrick, Balázs Halmos, Stephen V. Liu, Jianwei Che, Alexa B. Schrock, Alexander Drilon, Pasi A. Jänne, Mark M. Awad
Abstract
Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.