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Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells

Rebecca L Lloyd1,2, Paul W G Wijnhoven1, Antonio Ramos-Montoya1

  • 1Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.

Oncogene
|May 24, 2020
PubMed

Insights

The PARP inhibitor olaparib combined with ATR inhibitor AZD6738 shows synergistic cell death in ATM-deficient cancers. This combination therapy offers a faster, more effective treatment strategy than monotherapy, supporting clinical development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors like olaparib are FDA-approved for BRCA-mutated cancers.
  • Olaparib functions by inhibiting PARP1/2 and trapping PARP1 on DNA, leading to DNA damage that necessitates BRCA1/2-dependent repair.
  • Ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are crucial for DNA damage response and survival during PARP inhibition.

Purpose of the Study:

  • To investigate the synergistic potential of combining the PARP inhibitor olaparib with the ATR inhibitor AZD6738 (ceralasertib).
  • To elucidate the mechanistic basis for the combination's efficacy, particularly in ATM-deficient cancer models.
  • To evaluate the in vitro and in vivo effectiveness of the olaparib and AZD6738 combination therapy.

Main Methods:

  • In vitro studies using ATM-deficient cell lines treated with olaparib and/or AZD6738.
  • Cell cycle analysis to assess the impact of combination treatment on G2-M arrest.
  • Evaluation of chromosomal aberrations and cell death induction.
  • In vivo studies using xenograft and patient-derived xenograft (PDX) mouse models with ATM loss.

Main Results:

  • Olaparib and AZD6738 demonstrated synergistic cell death in ATM-deficient cells.
  • Combination therapy released cells from olaparib-induced G2-M arrest and led to increased chromosomal aberrations.
  • The combination achieved efficacy at lower concentrations and earlier time points compared to monotherapy.
  • Cell death occurred within 1-2 cell divisions, suggesting a faster mechanism than prolonged PARP inhibition.
  • In vivo studies confirmed the combination's activity in ATM-deficient xenograft and PDX models.

Conclusions:

  • Combined olaparib and AZD6738 treatment exhibits potent synergistic anti-cancer activity in ATM-deficient models.
  • This combination therapy offers a potentially more rapid and effective treatment strategy by inducing cell death within fewer cell divisions.
  • The findings provide a mechanistic rationale and support the clinical development of AZD6738 in combination with olaparib for ATM-deficient cancers.

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