CDK4/6i reverse PARPi resistance by targeting the E2F1- MCM2/5 pathway

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPis) like niraparib represents a major therapeutic challenge in ovarian cancer (OC). This study elucidates a novel resistance mechanism driven by the minichromosome maintenance proteins 2 and 5 (MCM2/5). In niraparib-resistant (NirR) OC cells, RNA-seq revealed upregulation of MCM2 and MCM5, which was functionally linked to enhanced proliferation and homologous recombination repair. Co-immunoprecipitation confirmed strengthened MCM2/5 interaction in NirR cells. Genetic knockdown of MCM2/5 resensitized NirR cells to niraparib, while their overexpression conferred resistance in parental cells. Mechanistically, the upregulation of MCM2/5 was transcriptionally regulated by the E2F1 transcription factor, activated via the CDK4/6-RB pathway. Consequently, pharmacological inhibition of CDK4/6 downregulated MCM2/5 expression and, when combined with niraparib, synergistically suppressed NirR tumor growth both in vitro and in vivo. Our findings identify the MCM2/5 complex as a critical mediator of PARPi resistance and establish the therapeutic potential of combining PARPis with CDK4/6 inhibitors to overcome this resistance in ovarian cancer.