Amplification of CRKL Induces Transformation and Epidermal Growth Factor Receptor Inhibitor Resistance in Human Non-Small Cell Lung Cancers

被引：117

作者：

Cheung, Hiu Wing ^{[1
,8
]}

Du, Jinyan ^{[2
,8
]}

Boehm, Jesse S. ^{[8
]}

He, Frank ^{[2
,8
]}

Weir, Barbara A. ^{[1
,8
]}

Wang, Xiaoxing ^{[1
,8
]}

Butaney, Mohit ^{[1
,3
]}

Sequist, Lecia V. ^{[5
]}

Luo, Biao ^{[8
]}

Engelman, Jeffrey A. ^{[5
]}

Root, David E. ^{[8
]}

Meyerson, Matthew ^{[1
,4
,6
,8
]}

Golub, Todd R. ^{[2
,4
,8
]}

Jaenne, Pasi A. ^{[1
,3
]}

Hahn, William C. ^{[1
,4
,7
,8
]}

机构：

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

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

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

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

[5] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

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

[7] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA

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

来源：

CANCER DISCOVERY | 2011年 / 1卷 / 07期

基金：

美国国家卫生研究院;

关键词：

CHRONIC MYELOGENOUS LEUKEMIA; ANAPLASTIC LYMPHOMA KINASE; PROTEIN-KINASE; HEMATOPOIETIC-CELLS; SIGNALING PATHWAYS; INDUCED ACTIVATION; ADAPTER PROTEIN; SH3; DOMAIN; MAP KINASE; FACTOR C3G;

D O I：

10.1158/2159-8290.CD-11-0046

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal-regulated kinase and AKT signaling. We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy. SIGNIFICANCE: These studies credential CRKL as an oncogene in a subset of NSCLC. Overexpression of CRKL induces cell transformation and resistance to epidermal growth factor receptor inhibitor treatment and suggest that therapeutic interventions targeting CRKL may confer a clinical benefit in a defined subset of NSCLCs. Cancer Discovery; 1(7); 608-25. (C) 2011 AACR.

引用

页码：608 / 625

页数：18

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