SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

被引：223

作者：

Fedele, Carmine ^{[1
]}

Ran, Hao ^{[1
]}

Diskin, Brian ^{[2
]}

Wei, Wei ^{[1
]}

Jen, Jayu ^{[1
]}

Geer, Mitchell J. ^{[1
]}

Araki, Kiyomi ^{[1
]}

Ozerdem, Ugur ^{[3
]}

Simeone, Diane M. ^{[1
]}

Miller, George ^{[2
]}

Neel, Benjamin G. ^{[1
]}

Tang, Kwan Ho ^{[1
]}

机构：

[1] NYU, Sch Med, NYU Langone Hlth, Laura & Isaac Perlmutter Canc Ctr, New York, NY 10016 USA

[2] NYU, Sch Med, NYU Langone Hlth, S Arthur Localio Lab,Dept Surg, New York, NY 10016 USA

[3] NYU, Sch Med, NYU Langone Hlth, Dept Pathol, New York, NY 10016 USA

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 10期

关键词：

KRAS-MUTANT LUNG; MUTATIONAL LANDSCAPE; SIGNALING PATHWAYS; BREAST-CANCER; COLON-CANCER; CELL-LINES; K-RAS; PHOSPHATASE; TUMORS; ACTIVATION;

D O I：

10.1158/2159-8290.CD-18-0444

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies. SIGNIFICANCE: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. (C) 2018 AACR.

引用

页码：1237 / 1249

页数：13

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