Dual Inhibition Of VEGF And PARP Suppresses KRAS-mutant Colorectal Cancer

Colon or rectal(colorectal)cancer(CRC)is the second-leading cause of cancer-related mortality.The addition of bevacizumab to chemotherapy has prolonged overall and progression-free survival rates for metastatic colorectal cancer(mCRC).However,KRAS-mutant(KRAS-mut)CRC,lacking an ideal targeted agent,represents an inferior-response subgroup of patients.Olaparib is a small molecule inhibitor of the nuclear enzyme poly(ADP-ribose)polymerase(PARP)with potential chemosensitizing,radiosensitizing,and antineoplastic activities.Olaparib selectively binds to and inhibits PARP,inhibiting PARP-mediated repair of single strand DNA breaks.PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance.In the present study,we investigated a combination approach of bevacizumab+olaparib in KRAS-mut CRC in a preclinical setting.The combined therapy effectively prevented tumor growth in a KRAS-mut cancer cell-derived xenograft model,although this effect was not observed in vitro.Under bevacizumab treatment,we detected intratumor hypoxia and impaired homologous recombination repair(HRR),accompanied by vascular regression.We explored the underlying mechanism of this combined therapy by mimicking a hypoxic condition in vitro using cobalt chloride(CoCl2).The results showed that hypoxia induced HRR and therefore sensitized KRAS-mut CRC cell lines HCT-116,SW620,and Lovo to olaparib.Furthermore,under this hypoxic condition,olaparib could arrest the cell cycle in the G2/M phase and dramatically induce cell apoptosis in KRAS-mut CRC cells.Taken together,these results indicated that the combination of bevacizumab+olaparib could be a potential therapeutic approach in a KRAS-mut CRC cohort.