ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma

Anna Schmitt; Gero Knittel; Daniela Welcker; Tsun Po Yang; Julie George; Michael Nowak; Uschi Leeser; Reinhard Büttner; Sven Perner; Martin Peifer; Hans Christian Reinhardt

doi:10.1158/0008-5472.CAN-16-3398

ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma

Anna Schmitt^*, Gero Knittel, Daniela Welcker, Tsun Po Yang, Julie George, Michael Nowak, Uschi Leeser, Reinhard Büttner, Sven Perner, Martin Peifer, Hans Christian Reinhardt

^*Corresponding author for this work

Institute of Pathology

95 Citations (Scopus)

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.

Original language	English
Journal	Cancer Research
Volume	77
Issue number	11
Pages (from-to)	3040-3056
Number of pages	17
ISSN	0008-5472
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-3398
Publication status	Published - 01.06.2017

Funding

We are indebted to our patients, who provided primary material. We thank Alexandra Florin, Marion M?ller, and Ursula Rommerscheidt-Fu? from the Institute of Pathology, University Hospital Cologne, for their outstanding technical support. Some analyses conducted in this work were in parts based upon data that was generated by The Cancer Genome Atlas managed by the NCI and NHGRI. This work was supported by the Volkswagenstiftung (Lichtenberg Program; H.C. Reinhardt), the Deutsche Forschungsgemeinschaft (KFO-286; H. C. Reinhardt and M. Peifer), the Bundesministerium f?r Bildung und Forschung (SMOOSE; H. C. Reinhardt, M. Peifer, R. B?ttner and MILES, M. Peifer), the German federal state North Rhine Westphalia (NRW) as part of the EFRE initiative (grant LS-1-1-030a to H. C. Reinhardt), the Else Kr?ner-Fresenius Stiftung (EKFS-2014-A06 to H. C. Reinhardt), and the Deutsche Krebshilfe (111724 to H. C. Reinhardt). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1158/0008-5472.CAN-16-3398

Cite this

@article{0aacd66a3aec4c7faedebc1f60405d87,

title = "ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma",

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.",

author = "Anna Schmitt and Gero Knittel and Daniela Welcker and Yang, \{Tsun Po\} and Julie George and Michael Nowak and Uschi Leeser and Reinhard B{\"u}ttner and Sven Perner and Martin Peifer and Reinhardt, \{Hans Christian\}",

year = "2017",

month = jun,

day = "1",

doi = "10.1158/0008-5472.CAN-16-3398",

language = "English",

volume = "77",

pages = "3040--3056",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

TY - JOUR

T1 - ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma

AU - Schmitt, Anna

AU - Knittel, Gero

AU - Welcker, Daniela

AU - Yang, Tsun Po

AU - George, Julie

AU - Nowak, Michael

AU - Leeser, Uschi

AU - Büttner, Reinhard

AU - Perner, Sven

AU - Peifer, Martin

AU - Reinhardt, Hans Christian

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85020791212

U2 - 10.1158/0008-5472.CAN-16-3398

DO - 10.1158/0008-5472.CAN-16-3398

M3 - Journal articles

C2 - 28363999

AN - SCOPUS:85020791212

SN - 0008-5472

VL - 77

SP - 3040

EP - 3056

JO - Cancer Research

JF - Cancer Research

IS - 11

ER -

ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma

Abstract

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this