Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells

被引：22

作者：

Lee, Ho-June ^{[1
]}

Cao, Yi ^{[2
]}

Pham, Victoria ^{[3
]}

Blackwood, Elizabeth ^{[4
]}

Wilson, Catherine ^{[1
]}

Evangelista, Marie ^{[1
]}

Klijn, Christiaan ^{[2
]}

Stokoe, David ^{[1
]}

Settleman, Jeff ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2017年 / 16卷 / 04期

关键词：

ONCOGENE; IDENTIFICATION; SENSITIVITY; ADDICTION; CHK1; ATR;

D O I：

10.1158/1535-7163.MCT-16-0504

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras-MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify cancer patients that may benefit from Chk1-targeted therapy. (C)2017 AACR.

引用

页码：694 / 704

页数：11

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