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 RothschildDiptasri Mandal, Elena Kupert, Daniela Seminara, Avinash Viswanathan, Ramaswamy Govindan, John Minna, Marshall W. Anderson, Ming You

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish
Pages (from-to)4665-4670
Number of pages6
JournalCancer research
Volume67
Issue number10
DOIs
StatePublished - May 15 2007

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    Vikis, H., Sato, M., James, M., Wang, D., Wang, Y., Wang, M., Jia, D., Liu, Y., Bailey-Wilson, J. E., Amos, C. I., Pinney, S. M., Petersen, G. M., De Andrade, M., Yang, P., Wiest, J. S., Fain, P. R., Schwartz, A. G., Gazdar, A., Gaba, C., ... You, M. (2007). EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Cancer research, 67(10), 4665-4670. https://doi.org/10.1158/0008-5472.CAN-07-0217