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

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.

Automated summary

Depletion of RNR subunit p53R2 impairs HR repair and sensitizes BRCA1/2-WT cancer cells to PARP inhibition, while loss of p53R2 leads to a decrease of HR repair factor CtIP. Casein kinase II (CK2) phosphorylates p53R2 at ser20, activating RNR for dNTPs production. Pharmacologic inhibition of CK2-mediated phosphorylation of p53R2 compromises HR repair capacity, making BRCA1/2-WT cancer cells susceptible to PARP inhibition.