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

Oncogene volume 41, pages 5020–5031 (2022)Cite this article

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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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Fig. 1: Different treatment schemes cause distinct phenotypes of PARPi-resistant BRCA2-mutant PEO1 cell lines.
Fig. 2: PEO1/OlaJR restores its BRCA2 functionality by a heterozygous BRCA2 reversion mutation.
Fig. 3: Both PARPi-resistant PEO1 cell lines show intact HR repair.
Fig. 4: PARPi-resistant PEO1 cell lines slow fork progression through increasing unscheduled origin firing.
Fig. 5: PARPi-resistant BRCA2-deficient cells increase fork protection via suppressing EZH2/MUS81 pathway.
Fig. 6: Enhanced ABCB1-mediated drug efflux activity contributes to acquired PARPi resistance.

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Funding

This research was funded by the intramural research program of the CCR, NCI, NIH (ZIA BC011525 awarded to JL). This study was partly supported by an NIH/NCI grant (R37CA261987-01 awarded to BB).

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Author notes

  1. These authors contributed equally: Jung-Min Lee, Jayakumar R. Nair.

Authors and Affiliations

  1. Women’s Malignancies Branch (WMB), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA

    Tzu-Ting Huang, Nitasha Gupta, Jung-Min Lee & Jayakumar R. Nair

  2. Molecular Cytogenetic Core Facility, MCGP, CCR, NCI, NIH, Frederick, MD, USA

    Sandra Sczerba Burkett

  3. Center for Cancer Research Collaborative Bioinformatics Resource, CCR, NCI, NIH, Bethesda, MD, USA

    Mayank Tandon

  4. Department of OB/GYN, Division of Reproductive Sciences, The University of Colorado, Aurora, CO, USA

    Tomomi M. Yamamoto & Benjamin G. Bitler

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  1. Tzu-Ting Huang
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Contributions

Methodology: TH, SB, MT,JN and JL; Formal analysis: TH and JN; Investigation: TH, JN, and JL; Writing—original draft preparation: TH and JN; Writing—review and editing: TH, SB, MT, TY, NG, BB, JL, and JN; Supervision: JL and JN; Funding acquisition: BB and JL. All authors have read and agreed to the published version of the paper.

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Correspondence to Jung-Min Lee.

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Huang, TT., Burkett, S.S., Tandon, M. et al. Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer. Oncogene 41, 5020–5031 (2022). https://doi.org/10.1038/s41388-022-02491-8

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