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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Synergism between ATM and PARP1 inhibition involves DNA damage and abrogating the G2 DNA damage checkpoint

Joyce P.Y. Mak, Hoi Tang Ma and Randy Y.C. Poon
Joyce P.Y. Mak
Division of Life Science, Hong Kong University of Science and Technology
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  • ORCID record for Joyce P.Y. Mak
Hoi Tang Ma
Division of Life Science, Hong Kong University of Science and Technology
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Randy Y.C. Poon
Division of Life Science, Hong Kong University of Science and Technology
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  • For correspondence: rycpoon@ust.hk
DOI: 10.1158/1535-7163.MCT-19-0474
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Abstract

PARP inhibitors have emerged as effective chemotherapeutic agents for BRCA1/BRCA2-deficient cancers. Another DNA damage response protein ATM is also increasingly being recognized as a target for synthetic lethality with PARP inhibitors. As ATM functions in both cell cycle arrest and DNA repair after DNA damage, how cells respond to inhibition of ATM and PARP1 is yet to be defined precisely. We found that loss of ATM function, either in an ATM-deficient background or after treatment with ATM inhibitors (KU-60019 or AZD0156), results in spontaneous DNA damage and an increase in PARylation. When PARP1 is also deleted or inhibited with inhibitors (olaparib or veliparib), the massive increase in DNA damage activates the G2 DNA damage checkpoint kinase cascade involving ATR, CHK1/2, and WEE1. Our data indicated that the role of ATM in DNA repair is critical for the synergism with PARP inhibitors. Bypass of the G2 DNA damage checkpoint in the absence of ATM functions occurs only after a delay. The relative insensitivity of PARP1-deficient cells to PARP inhibitors suggested that other PARP isoforms played a relatively minor role in comparison to PARP1 in synergism with ATMi. As deletion of PARP1 also increased sensitivity to ATM inhibitors, trapping of PARP1 on DNA may not be the only mechanism involved in the synergism between PARP1 and ATM inhibition. Collectively, these studies provide a mechanistic foundation for therapies targeting ATM and PARP1.

  • Received May 4, 2019.
  • Revision received August 25, 2019.
  • Accepted October 2, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst October 9, 2019
doi: 10.1158/1535-7163.MCT-19-0474

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Synergism between ATM and PARP1 inhibition involves DNA damage and abrogating the G2 DNA damage checkpoint
Joyce P.Y. Mak, Hoi Tang Ma and Randy Y.C. Poon
Mol Cancer Ther October 9 2019 DOI: 10.1158/1535-7163.MCT-19-0474

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Synergism between ATM and PARP1 inhibition involves DNA damage and abrogating the G2 DNA damage checkpoint
Joyce P.Y. Mak, Hoi Tang Ma and Randy Y.C. Poon
Mol Cancer Ther October 9 2019 DOI: 10.1158/1535-7163.MCT-19-0474
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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