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PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality-An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness.

Abstract
Poly (ADP-ribose) polymerase inhibitor (PARPi, olaparib) impairs the repair of DNA single-strand breaks (SSBs), resulting in double-strand breaks (DSBs) that cannot be repaired efficiently in homologous recombination repair (HRR)-deficient cancers such as BRCA1/2-mutant cancers, leading to synthetic lethality. Despite the efficacy of olaparib in the treatment of BRCA1/2 deficient tumors, PARPi resistance is common. We hypothesized that the combination of olaparib with anticancer agents that disrupt HRR by targeting ataxia telangiectasia and Rad3-related protein (ATR) or checkpoint kinase 1 (CHK1) may be an effective strategy to reverse ovarian cancer resistance to olaparib. Here, we evaluated the effect of olaparib, the ATR inhibitor AZD6738, and the CHK1 inhibitor MK8776 alone and in combination on cell survival, colony formation, replication stress response (RSR) protein expression, DNA damage, and apoptotic changes in BRCA2 mutated (PEO-1) and HRR-proficient BRCA wild-type (SKOV-3 and OV-90) cells. Combined treatment caused the accumulation of DNA DSBs. PARP expression was associated with sensitivity to olaparib or inhibitors of RSR. Synergistic effects were weaker when olaparib was combined with CHK1i and occurred regardless of the BRCA2 status of tumor cells. Because PARPi increases the reliance on ATR/CHK1 for genome stability, the combination of PARPi with ATR inhibition suppressed ovarian cancer cell growth independently of the efficacy of HRR. The present results were obtained at sub-lethal doses, suggesting the potential of these inhibitors as monotherapy as well as in combination with olaparib.
AuthorsPatrycja Gralewska, Arkadiusz Gajek, Agnieszka Marczak, Michał Mikuła, Jerzy Ostrowski, Agnieszka Śliwińska, Aneta Rogalska
JournalInternational journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 24 (Dec 19 2020) ISSN: 1422-0067 [Electronic] Switzerland
PMID33352723 (Publication Type: Journal Article)
Chemical References
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RNA, Small Interfering
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
Topics
  • Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, genetics, metabolism)
  • BRCA1 Protein (genetics)
  • BRCA2 Protein (genetics)
  • Checkpoint Kinase 1 (antagonists & inhibitors, genetics, metabolism)
  • Cystadenocarcinoma, Serous (drug therapy, genetics, pathology)
  • Female
  • Homologous Recombination
  • Humans
  • Ovarian Neoplasms (drug therapy, genetics, pathology)
  • Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
  • RNA, Small Interfering (genetics)
  • Signal Transduction
  • Synthetic Lethal Mutations

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