ATM Deficiency Is Associated with Sensitivity to PARP1-and ATR Inhibitors in Lung Adenocarcinoma

被引：88

作者：

Schmitt, Anna ^{[1
,2
]}

Knittel, Gero ^{[1
,2
]}

Welcker, Daniela ^{[1
,2
]}

Yang, Tsun-Po ^{[3
,4
]}

George, Julie ^{[3
]}

Nowak, Michael ^{[5
]}

Leeser, Uschi ^{[1
,2
]}

Buettner, Reinhard ^{[6
]}

Perner, Sven ^{[7
,8
,9
,10
]}

Peifer, Martin ^{[3
,4
]}

Reinhardt, Hans Christian ^{[1
,2
,4
]}

机构：

[1] Univ Hosp Cologne, Dept Internal Med 1, Weyertal 115B, D-50931 Cologne, Germany

[2] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[3] Univ Cologne, Dept Translat Gen, Ctr Integrated Oncol Cologne Bonn, Fac Med, Cologne, Germany

[4] Univ Cologne, CMMC, Cologne, Germany

[5] Univ Hosp Bonn, Inst Pathol, Bonn, Germany

[6] Univ Hosp Cologne, Inst Pathol, Cologne, Germany

[7] Univ Med Ctr Schleswig Holstein, Dept Pathol, Campus Luebeck, Lubeck, Germany

[8] Univ Med Ctr Schleswig Holstein, Dept Pathol, Campus Luebeck, Borstel, Germany

[9] Leibniz Ctr Med & Biosci, Res Ctr Borstel, Lubeck, Germany

[10] Leibniz Ctr Med & Biosci, Res Ctr Borstel, Borstel, Germany

来源：

CANCER RESEARCH | 2017年 / 77卷 / 11期

关键词：

DOUBLE-STRAND BREAKS; DNA-REPAIR PATHWAYS; HOMOLOGOUS RECOMBINATION; P53-DEFICIENT CELLS; CELLULAR-RESPONSE; CANCER; CHECKPOINT; P53; CHEMOTHERAPY; CISPLATIN;

D O I：

10.1158/0008-5472.CAN-16-3398

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. (C) 2017 AACR.

引用

页码：3040 / 3056

页数：17

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