EML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors

被引：904

作者：

Choi, Young Lim ^{[1
,2
]}

Soda, Manabu ^{[1
]}

Yamashita, Yoshihiro ^{[1
]}

Ueno, Toshihide ^{[1
]}

Takashima, Junpei ^{[3
]}

Nakajima, Takahiro ^{[4
]}

Yatabe, Yasushi ^{[5
]}

Takeuchi, Kengo ^{[7
]}

Hamada, Toru ^{[1
]}

Haruta, Hidenori ^{[1
]}

Ishikawa, Yuichi ^{[8
]}

Kimura, Hideki ^{[4
]}

Mitsudomi, Tetsuya ^{[6
]}

Tanio, Yoshiro ^{[3
]}

Mano, Hiroyuki ^{[1
,2
,9
]}

机构：

[1] Jichi Med Univ, Div Funct Genom, Shimotsuke, Tochigi 3290498, Japan

[2] Univ Tokyo, Grad Sch Med, Dept Med Genom, Tokyo, Japan

[3] Osaka Gen Med Ctr, Dept Internal Med, Osaka, Japan

[4] Chiba Canc Ctr, Div Thorac Dis, Chiba 2608717, Japan

[5] Aichi Canc Ctr Hosp, Dept Pathol, Aichi, Japan

[6] Aichi Canc Ctr Hosp, Dept Thorac Surg, Aichi, Japan

[7] Japanese Fdn Canc Res, Inst Canc, Pathol Project Mol Targets, Tokyo 170, Japan

[8] Japanese Fdn Canc Res, Inst Canc, Div Pathol, Tokyo 170, Japan

[9] Japan Sci & Technol Agcy, Saitama, Japan

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2010年 / 363卷 / 18期

基金：

日本学术振兴会;

关键词：

CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE; ACQUIRED-RESISTANCE; IMATINIB; IDENTIFICATION; GEFITINIB; FUSION; DOMAIN; ABL; EFFICACY;

D O I：

10.1056/NEJMoa1007478

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1734 / 1739

页数：6

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