Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer

  • Oncogene. 2022 Oct 12. doi: 10.1038/s41388-022-02491-8.
Tzu-Ting Huang  1 ,  Sandra Sczerba Burkett  2 ,  Mayank Tandon  3 ,  Tomomi M Yamamoto  4 ,  Nitasha Gupta  1 ,  Benjamin G Bitler  4 ,  Jung-Min Lee  #  5 ,  Jayakumar R Nair  #  1
Affiliations
  • 1. Women's Malignancies Branch (WMB), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.
  • 2. Molecular Cytogenetic Core Facility, MCGP, CCR, NCI, NIH, Frederick, MD, USA.
  • 3. Center for Cancer Research Collaborative Bioinformatics Resource, CCR, NCI, NIH, Bethesda, MD, USA.
  • 4. Department of OB/GYN, Division of Reproductive Sciences, The University of Colorado, Aurora, CO, USA.
  • 5. Women's Malignancies Branch (WMB), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. [email protected].
  • # Contributed equally.
PMID: 36224341 DOI: 10.1038/s41388-022-02491-8
Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian Cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/Chk1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian Cancer.

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