CK2 inhibition sensitizes BRCA-proficient cancer cells to PARP inhibitors by modulating PRIMPOL-mediated repriming

CK2 is a constitutively active Ser/Thr kinase that is widely expressed across eukaryotes. Recent studies have highlighted its crucial role in ensuring optimal activation of the ATR-CHK1 checkpoint pathway during replication stress and in maintaining genome integrity by ensuring the WRN-RPA interaction. Here, we identify a novel role of CK2 in restraining the PrimPol-mediated repriming mechanism. Using a functional inhibitor of CK2, we demonstrate that the absence of its activity during mild replicative stress, which slows down fork progression, leads to massive PrimPol recruitment at the replication fork and excessive activation of the repriming pathway. The accumulation of replication gaps, resulting from MRE11-mediated processing of nicked DNA left by repriming, can act as a sensitizer to PARP inhibitor treatment, similarly to what occurs in BRCA-deficient cancer cells. Based on these findings, we evaluated the therapeutic potential of CK2 inhibition. Our results show that co-treatment of Olaparib-resistant, BRCA-proficient cancer cells with an CK2 inhibitor and Olaparib reduces cell viability and proliferation, suggesting a promising therapeutic strategy.