EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity
Haris Vikis, Mitsuo Sato, Michael James, Daolong Wang, Yian Wang, Min Wang, Dongmei Jia, Yan Liu, Joan E Bailey-Wilson, Christopher I Amos, Susan M Pinney, Gloria M Petersen, Mariza de Andrade, Ping Yang, Jonathan S Wiest, Pamela R Fain, Ann G Schwartz, Adi Gazdar, Colette Gaba, Henry Rothschild, Diptasri Mandal, Elena Kupert, Daniela Seminara, Avinash Viswanathan, Ramaswamy Govindan, John Minna, Marshall W Anderson, Ming You, Haris Vikis, Mitsuo Sato, Michael James, Daolong Wang, Yian Wang, Min Wang, Dongmei Jia, Yan Liu, Joan E Bailey-Wilson, Christopher I Amos, Susan M Pinney, Gloria M Petersen, Mariza de Andrade, Ping Yang, Jonathan S Wiest, Pamela R Fain, Ann G Schwartz, Adi Gazdar, Colette Gaba, Henry Rothschild, Diptasri Mandal, Elena Kupert, Daniela Seminara, Avinash Viswanathan, Ramaswamy Govindan, John Minna, Marshall W Anderson, Ming You
Abstract
The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer.
Figures
Source: PubMed