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Synergism between ATM and PARP1 Inhibition Involves DNA Damage and Abrogating the G2 DNA Damage Checkpoint

Joyce P Y Mak1, Hoi Tang Ma1, Randy Y C Poon2

  • 1Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Molecular Cancer Therapeutics
|October 11, 2019
PubMed

Insights

Inhibiting ATM and PARP1 together causes significant DNA damage, activating cell cycle checkpoints. ATM

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors are effective for BRCA1/BRCA2-deficient cancers.
  • ATM protein is a potential target for synthetic lethality with PARP inhibitors.
  • The cellular response to combined ATM and PARP1 inhibition requires precise definition.

Purpose of the Study:

  • To elucidate the precise cellular response to combined inhibition of ATM and PARP1.
  • To investigate the role of ATM in DNA repair for synergism with PARP inhibitors.
  • To explore the mechanisms underlying the synergistic effects of ATM and PARP1 inhibition.

Main Methods:

  • Utilized ATM-deficient cell lines and ATM inhibitors (KU-60019, AZD0156).
  • Employed PARP1 deletion and PARP inhibitors (olaparib, veliparib).
  • Analyzed DNA damage, PARylation levels, and G2 DNA damage checkpoint activation (ATR, CHK1/2, WEE1).

Main Results:

  • Loss of ATM function leads to spontaneous DNA damage and increased PARylation.
  • Combined ATM and PARP1 inhibition activates the G2 DNA damage checkpoint cascade.
  • ATM's role in DNA repair is critical for synergism with PARP inhibitors.
  • PARP1 inhibition is more critical than other PARP isoforms for this synergism.
  • PARP1 deletion enhances sensitivity to ATM inhibitors, suggesting mechanisms beyond PARP1 trapping.

Conclusions:

  • ATM inhibition combined with PARP1 inhibition induces significant DNA damage and activates checkpoints.
  • ATM's DNA repair function is essential for the synergistic effect with PARP inhibitors.
  • The findings provide a mechanistic basis for targeting ATM and PARP1 concurrently in cancer therapy.

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