CDK4/6i reverse PARPi resistance by targeting the E2F1- MCM2/5 pathway - PubMed
4 days ago
- #ovarian cancer
- #PARP inhibitors
- #CDK4/6 inhibitors
- CDK4/6 inhibitors (CDK4/6i) can reverse resistance to PARP inhibitors (PARPis) like niraparib in ovarian cancer (OC).
- Resistance to PARPis is linked to upregulation of minichromosome maintenance proteins 2 and 5 (MCM2/5) in niraparib-resistant (NirR) OC cells.
- MCM2/5 upregulation enhances proliferation and homologous recombination repair, contributing to PARPi resistance.
- The interaction between MCM2/5 is strengthened in NirR cells, and knockdown of MCM2/5 resensitizes these cells to niraparib.
- E2F1 transcription factor, activated via the CDK4/6-RB pathway, transcriptionally regulates MCM2/5 upregulation.
- Combining CDK4/6 inhibitors with PARPis synergistically suppresses NirR tumor growth in vitro and in vivo.
- The study highlights the therapeutic potential of targeting the CDK4/6-RB-E2F1-MCM2/5 pathway to overcome PARPi resistance in OC.