Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells

被引：77

作者：

Teng, Pang-ning ^{[1
]}

Bateman, Nicholas W. ^{[1
]}

Darcy, Kathleen M. ^{[1
]}

Hamilton, Chad A. ^{[1
,2
]}

Maxwell, George Larry ^{[1
,3
]}

Bakkenist, Christopher J. ^{[4
,5
]}

Conrads, Thomas P. ^{[1
]}

机构：

[1] Womens Hlth Integrated Res Ctr Inova Hlth Syst, Gynecol Canc Ctr Excellence, Dept Def, Annandale, VA 22003 USA

[2] Walter Reed Natl Mil Med Ctr, Dept Obstet & Gynecol, Gynecol Oncol Serv, Bethesda, MD USA

[3] Inova Fairfax Hosp, Dept Obstet & Gynecol, Fairfax, VA USA

[4] Univ Pittsburgh, Sch Med, Dept Radiat Biol, Pittsburgh, PA 15261 USA

[5] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA

来源：

GYNECOLOGIC ONCOLOGY | 2015年 / 136卷 / 03期

关键词：

DNA damage repair response; ATR; ATM; Gynecologic cancer; Cisplatin resistance; Ionizing radiation; P53; GENE; DNA; KINASE; REPAIR; IDENTIFICATION; PATHWAYS; SURVIVAL; PHOSPHORYLATION; RECOMBINATION; SENSITIVITY;

D O I：

10.1016/j.ygyno.2014.12.035

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Objective. Significant reductions in gynecologic (GYN) cancer mortality and morbidity require treatments that prevent and reverse resistance to chemotherapy and radiation. The objective of this study was to determine if pharmacologic inhibition of key DNA damage response kinases in GYN cancers would enhance cell killing by platinum-based chemotherapy and radiation. Methods. A panel of human ovarian, endometrial and cervical cancer cell lines were treated with platinum drugs or ionizing radiation (IR) along with small molecule pharmacological kinase inhibitors of Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR). Results. Pharmacologic inhibition of ATR significantly enhanced platinum drug response in all GYN cancer cell lines tested, whereas inhibition of ATM did not enhance the response to platinum drugs. Co-inhibition of ATM and ATR did not enhance platinum kill beyond that observed by inhibition of ATR alone. By contrast, inhibiting either ATR or ATM enhanced the response to IR in all GYN cancer cells, with further enhancement achieved with co-inhibition. Conclusions. These studies highlight actionable mechanisms operative in GYN cancer cells with potential to maximize response of platinum agents and radiation in newly diagnosed as well as recurrent gynecologic cancers. (C) 2014 Elsevier Inc. All rights reserved.

引用

页码：554 / 561

页数：8

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