Young Lim Choi, M.D., Ph.D., Manabu Soda, M.D., Ph.D., Yoshihiro Yamashita, M.D., Ph.D., Toshihide Ueno, Ph.D., Junpei Takashima, M.D., Takahiro Nakajima, M.D., Ph.D., Yasushi Yatabe, M.D., Ph.D., Kengo Takeuchi, M.D., Ph.D., Toru Hamada, M.D., Hidenori Haruta, M.D., Ph.D., Yuichi Ishikawa, M.D., Ph.D., Hideki Kimura, M.D., Ph.D., Tetsuya Mitsudomi, M.D., Ph.D., Yoshiro Tanio, M.D., Ph.D., and Hiroyuki Mano, M.D., Ph.D. for the ALK Lung Cancer Study Group. N Engl J Med 2010; 363:1734-1739October 28, 2010
The EML4 (echinoderm microtubule-associated protein-like 4)–ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non–small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way.
Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.)
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