Data from Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors
Year: 2024
Type: other
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.
Authors: Federica Pecci, Seshiru Nakazawa, Biagio Ricciuti, Guilherme Harada, Jessica K. Lee, Joao V. Alessi, Adriana Barrichello, Victor R. Vaz, Giuseppe Lamberti, Alessandro Di Federico, Malini M. 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, Patrick C. Ma, Balazs Halmos, Stephen V. Liu, Jianwei Che, Alexa B. Schrock, Alexander Drilon, Pasi A. Jänne, Mark M. Awad
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4401274155