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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

1
Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, 90-236 Lodz, Poland
2
Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
3
Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland
4
Department of Nucleic Acid Biochemistry, Medical University of Lodz, 92-213 Lodz, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(24), 9715; https://doi.org/10.3390/ijms21249715
Received: 4 November 2020 / Revised: 14 December 2020 / Accepted: 16 December 2020 / Published: 19 December 2020
(This article belongs to the Special Issue DNA Replication Stress and Chromosomal Instability)
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. View Full-Text
Keywords: ATR inhibitor; CHK1 inhibitor; ovarian cancer; PARP inhibitor; targeted therapy ATR inhibitor; CHK1 inhibitor; ovarian cancer; PARP inhibitor; targeted therapy
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MDPI and ACS Style

Gralewska, P.; Gajek, A.; Marczak, A.; Mikuła, M.; Ostrowski, J.; Śliwińska, A.; Rogalska, A. 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. Int. J. Mol. Sci. 2020, 21, 9715. https://doi.org/10.3390/ijms21249715

AMA Style

Gralewska P, Gajek A, Marczak A, Mikuła M, Ostrowski J, Śliwińska A, Rogalska A. 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. International Journal of Molecular Sciences. 2020; 21(24):9715. https://doi.org/10.3390/ijms21249715

Chicago/Turabian Style

Gralewska, Patrycja; Gajek, Arkadiusz; Marczak, Agnieszka; Mikuła, Michał; Ostrowski, Jerzy; Śliwińska, Agnieszka; Rogalska, Aneta. 2020. "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" Int. J. Mol. Sci. 21, no. 24: 9715. https://doi.org/10.3390/ijms21249715

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