Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC

被引：943

作者：

Turke, Alexa B. ^{[1
,2
]}

Zejnullahu, Kreshnik ^{[3
,4
]}

Wu, Yi-Long ^{[5
,6
]}

Song, Youngchul ^{[1
]}

Dias-Santagata, Dora ^{[1
]}

Lifshits, Eugene ^{[1
]}

Toschi, Luca ^{[3
,4
]}

Rogers, Andrew ^{[3
,4
]}

Mok, Tony ^{[7
]}

Sequist, Lecia ^{[1
]}

Lindeman, Neal I. ^{[8
]}

Murphy, Carly ^{[8
]}

Akhavanfard, Sara ^{[1
]}

Yeap, Beow Y. ^{[1
,2
]}

Xiao, Yun ^{[4
,8
]}

Capelletti, Marzia ^{[3
,4
]}

Iafrate, A. John ^{[1
]}

Lee, Charles ^{[8
]}

Christensen, James G. ^{[9
]}

Engelman, Jeffrey A. ^{[1
,2
]}

Jaenne, Pasi A. ^{[2
,3
,4
,10
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA

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

[3] Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

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

[5] Guangdong Gen Hosp, Guangdong Lung Canc Inst, Guangzhou, Guangdong, Peoples R China

[6] Guangdong Gen Hosp, Ctr Canc, Guangzhou, Guangdong, Peoples R China

[7] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China

[8] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Pfizer Global Res & Dev, Dept Res Pharmacol, La Jolla Labs, La Jolla, CA 92121 USA

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

来源：

CANCER CELL | 2010年 / 17卷 / 01期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR-RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; CHRONIC MYELOID-LEUKEMIA; PROSPECTIVE PHASE-II; ACQUIRED-RESISTANCE; GEFITINIB RESISTANCE; DOMAIN MUTATIONS; T790M MUTATIONS; GENE MUTATION;

D O I：

10.1016/j.ccr.2009.11.022

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations; of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.

引用

页码：77 / 88

页数：12

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