Abstract
Pancreatic ductal adenocarcinoma (PDAC) shows limited response to chemotherapy, partly due to the absence of effective biomarkers for personalized treatment. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 90% of PDAC cases, and tumors dependent on KRAS (dKRAS) can be identified using gene expression signature scores. Previous research indicates that dKRAS-PDAC cells are sensitive to decitabine (DEC), an FDA-approved drug for hematological cancers, though its use in solid tumors is limited by side effects. We discovered that low-dose DEC combined with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) enhances antitumor activity in dKRAS-PDAC. DEC induces DNA damage and activates the ataxia telangiectasia (ATR)/ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR), with PARP1-mediated repair playing a key role. Inhibiting PARP with OLA further improves efficacy, even in BRCA1/2-wild-type and homologous recombination (HR)-proficient tumors but not in KRAS-independent tumors. The combination was especially effective in dKRAS-PDAC with a BRCA2 mutation, preventing metastasis growth. Our results support the clinical evaluation of DEC+OLA in PDAC.