Cetuximab Response of Lung Cancer-Derived EGF Receptor Mutants Is Associated with Asymmetric Dimerization

被引：93

作者：

Cho, Jeonghee ^{[1
,3
,9
]}

Chen, Liang ^{[1
]}

Sangji, Naveen ^{[1
,3
]}

Okabe, Takafumi ^{[1
,4
]}

Yonesaka, Kimio ^{[1
,4
]}

Francis, Joshua M. ^{[1
,3
]}

Flavin, Richard J. ^{[1
,5
]}

Johnson, William ^{[1
,3
]}

Kwon, Jihyun ^{[9
]}

Yu, Soyoung ^{[1
,2
]}

Greulich, Heidi ^{[1
,6
,10
]}

Johnson, Bruce E. ^{[1
,4
,6
]}

Eck, Michael J. ^{[2
,7
]}

Jaenne, Pasi A. ^{[1
,4
,6
]}

Wong, Kwok-Kin ^{[1
,6
]}

Meyerson, Matthew ^{[1
,3
,8
,10
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

[5] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[9] Samsung Med Ctr, Samsung Genome Inst, Seoul 135270, South Korea

[10] Broad Inst Harvard & MIT, Cambridge, MA USA

来源：

CANCER RESEARCH | 2013年 / 73卷 / 22期

关键词：

GROWTH-FACTOR RECEPTOR; KINASE DOMAIN; TYROSINE KINASE; WILD-TYPE; GEFITINIB; MUTATIONS; ACTIVATION; SENSITIVITY; RESISTANCE; INHIBITION;

D O I：

10.1158/0008-5472.CAN-13-1145

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Kinase domain mutations of the EGF receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here, we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. We show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. In addition, treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization-dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization-independent EGFR mutants. These data imply that different EGFR mutants show differential requirements for dimerization and that disruption of dimerization may be among the antitumor mechanisms of cetuximab. (C) 2013 AACR.

引用

页码：6770 / 6779

页数：10

共 54 条

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[Anonymous], J CLIN ONCOL S

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