CDCA5 knockdown potentiates olaparib sensitivity in BRCA1-mutated ovarian cancer through autophagy activation.

BACKGROUND: BRCA1-mutated ovarian cancer poses substantial therapeutic hurdles due to its poor prognosis and resistance to traditional therapies. Although acquired resistance is still a significant obstacle, PARP inhibitors, e.g., olaparib, have demonstrated promise in prolonging progression-free survival (PFS) in these individuals. The therapeutic potential of CDCA5 silencing in conjunction with olaparib to improve treatment effectiveness for ovarian cancer with a BRCA1 mutation is examined in this study. METHODS: Using BRCA1-mutated ovarian cancer cell lines (UWB1.289 and SNU251) and xenograft models, we analyzed the effects of CDCA5 knockdown alone or combined with olaparib. Functional assays (CCK-8, immunofluorescence, TEM, western blot) evaluated proliferation, autophagy, DNA damage, and PI3K/AKT/mTOR signaling. RESULTS: CDCA5 knockdown inhibited proliferation, activated autophagy, and induced DNA damage in BRCA1-mutated cells. Moreover, combination with olaparib synergistically enhanced these effects, with significant tumor growth inhibition in vivo. Mechanistically, the combination suppressed the PI3K/AKT/mTOR pathway, promoting autophagy and exacerbating DNA damage. Pharmacological activation of PI3K/AKT/mTOR reversed these antitumor effects. CONCLUSIONS: The anticancer effects of olaparib are enhanced by CDCA5 knockdown, which also promotes autophagy and exacerbates DNA damage via the PI3K/AKT/mTOR pathway. These findings provide a novel therapeutic approach for treating BRCA1-mutated ovarian cancer that overcomes PARP inhibitor resistance and enhances treatment results.