Universität zu Köln

Schmitt, Anna, Knittel, Gero, Welcker, Daniela, Yang, Tsun-Po ORCID: 0000-0002-9077-4434, George, Julie, Nowak, Michael, Leeser, Uschi, Buettner, Reinhard, Perner, Sven, Peifer, Martin ORCID: 0000-0002-5243-5503 and Reinhardt, Hans Christian (2017). ATM Deficiency Is Associated with Sensitivity to PARP1-and ATR Inhibitors in Lung Adenocarcinoma. Cancer Res., 77 (11). S. 3040 - 3057. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schmitt, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Knittel, Gero UNSPECIFIED UNSPECIFIED UNSPECIFIED Welcker, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, Tsun-Po UNSPECIFIED orcid.org/0000-0002-9077-4434 UNSPECIFIED George, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Nowak, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Leeser, Uschi UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Perner, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Reinhardt, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-229180
DOI:	10.1158/0008-5472.CAN-16-3398
Journal or Publication Title:	Cancer Res.
Volume:	77
Number:	11
Page Range:	S. 3040 - 3057
Date:	2017
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DOUBLE-STRAND BREAKS; DNA-REPAIR PATHWAYS; HOMOLOGOUS RECOMBINATION; P53-DEFICIENT CELLS; CELLULAR-RESPONSE; CANCER; CHECKPOINT; P53; CHEMOTHERAPY; CISPLATIN Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22918