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Targeting CK2-mediated phosphorylation of p53R2 sensitizes BRCA-proficient cancer cells to PARP inhibitors

Oncogene volume 42, pages 2971–2984 (2023)Cite this article

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Abstract

Poly[ADP-ribose] polymerase (PARP) inhibitors, which selectively kills homologous recombination (HR) repair-deficient cancer cells, are widely employed to treat cancer patients harboring BRCA1/2 mutations. However, they display limited efficacy in tumors with wild-type (WT) BRCA1/2. Thus, it is crucial to identify new druggable HR repair regulators and improve the therapeutic efficacy of PARP inhibitors via combination therapies in BRCA1/2-WT tumors. Here, we show that the depletion of ribonucleotide reductase (RNR) subunit p53R2 impairs HR repair and sensitizes BRCA1/2-WT cancer cells to PARP inhibition. We further demonstrate that the loss of p53R2 leads to a decrease of HR repair factor CtIP, as a result of dNTPs shortage-induced ubiquitination of CtIP. Moreover, we identify that casein kinase II (CK2) phosphorylates p53R2 at its ser20, which subsequently activates RNR for dNTPs production. Therefore, pharmacologic inhibition of the CK2-mediated phosphorylation of p53R2 compromises its HR repair capacity in BRCA1/2-WT cancer cells, which renders these cells susceptible to PARP inhibition in vitro and in vivo. Therefore, our study reveals a novel strategy to inhibit HR repair activity and convert BRCA1/2-proficient cancers to be susceptible to PARP inhibitors via synthetic lethal combination.

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Fig. 1: Knockout of p53R2 increases Olaparib sensitivity.
Fig. 2: p53R2 deficiency results in reduction of HR repair capacity.
Fig. 3: p53R2 depletion decreases CtIP via dNTPs deficiency.
Fig. 4: p53R2 is phosphorylated by CK2 at ser20.
Fig. 5: Ser20 phosphorylation of p53R2 affects HR repair and PARP inhibitor sensitivity.
Fig. 6: Inhibition of CK2 impairs HR repair activity and sensitizes BRCA1/2 WT cancer cells to PARP inhibitor.
Fig. 7: Combination treatment of CK2 inhibitor and olaparib induces synergistic anti-tumor efficacy in BRCA1/2 WT xenograft model.

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All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials and are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank to Dr. Congcong Chen (Jinan University) and Mr. Yanguan Guo (Jinan University) for their technique supports.

Funding

This work is supported by National Natural Science Foundation of China (82073042 to GC; 82272692 to DK. Li), Guangdong Basic and Applied Basic Research Foundation (2022B1515020105 to GC) and Natural Science Foundation of Zhejiang Province (LY21H160025 to YQ).

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  1. These authors contributed equally: Cong Wang, Ling Tian, Qiang He.

Authors and Affiliations

  1. School of Biopharmacy, China Pharmaceutical University, Nanjing, 211198, PR China

    Cong Wang, Bo Zhu & Guo Chen

  2. Department of Medical Biochemistry and Molecular Biology, School of Medicine Jinan University, Guangzhou, 510632, PR China

    Ling Tian, Qiang He, Shengbin Lin & Guo Chen

  3. Department of Gynecology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004, China

    Yue Wu & Dake Li

  4. The First Affiliated Hospital, Key Laboratory of Combined Multi-Organ Transplantation, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China

    Yiting Qiao

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The authors confirm contribution to the paper as follows: study conception and design: GC; data collection: CW, LT, QH, YW, SL; analysis and interpretation of results: GC, LT, QH, SL, CW, YQ; draft manuscript preparation: GC, QH, LT; supervision: GC, DL and BZ. All authors reviewed the results and approved the final version of the manuscript.

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Wang, C., Tian, L., He, Q. et al. Targeting CK2-mediated phosphorylation of p53R2 sensitizes BRCA-proficient cancer cells to PARP inhibitors. Oncogene 42, 2971–2984 (2023). https://doi.org/10.1038/s41388-023-02812-5

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