Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors

被引：243

作者：

Ercan, Dalia ^{[1
,2
]}

Xu, Chunxiao ^{[1
,3
]}

Yanagita, Masahiko ^{[1
,3
]}

Monast, Calixte S. ^{[11
]}

Pratilas, Christine A. ^{[12
,14
]}

Montero, Joan ^{[3
]}

Butaney, Mohit ^{[1
,3
]}

Shimamura, Takeshi ^{[1
,3
,15
]}

Sholl, Lynette ^{[8
]}

Ivanova, Elena V. ^{[5
]}

Tadi, Madhavi ^{[12
,14
]}

Rogers, Andrew ^{[1
,3
]}

Repellin, Claire ^{[1
,3
]}

Capelletti, Marzia ^{[1
,3
]}

Maertens, Ophelia ^{[7
,9
]}

Goetz, Eva M. ^{[2
,3
]}

Letai, Anthony ^{[3
]}

Garraway, Levi A. ^{[2
,3
,7
,10
]}

Lazzara, Matthew J. ^{[11
]}

Rosen, Neal ^{[13
,14
]}

Gray, Nathanael S. ^{[4
,6
]}

Wong, Kwok-Kin ^{[1
,3
,5
,7
]}

Jaenne, Pasi A. ^{[1
,3
,5
,7
]}

机构：

[1] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[4] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[5] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA

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

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

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

[9] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

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

[11] Univ Penn, Dept Chem & Biomol Engn, Philadelphia, PA 19104 USA

[12] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA

[13] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA

[14] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10021 USA

[15] Loyola Univ Chicago, Dept Mol Pharmacol & Therapeut, Inst Oncol, Stritch Sch Med, Maywood, IL USA

来源：

CANCER DISCOVERY | 2012年 / 2卷 / 10期

关键词：

GROWTH-FACTOR-RECEPTOR; CELL LUNG-CANCER; 1ST-LINE TREATMENT; MET AMPLIFICATION; T790M MUTATION; OPEN-LABEL; GEFITINIB; SENSITIVITY; PHOSPHORYLATION; CHEMOTHERAPY;

D O I：

10.1158/2159-8290.CD-12-0103

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP-ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non-small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.

引用

页码：934 / 947

页数：14

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