Drug Resistance Mechanisms in Ovarian Cancer

Ovarian cancer, as the leading cause of mortality among gynecological malignancies, mainly relies on platinum-based drugs and taxanes for chemotherapy. The drug resistance that develops during the treatment process is the core bottleneck leading to treatment failure, tumor recurrence, and a significant decline in survival rate for patients. The mechanism of drug resistance involves multiple aspects. Abnormal drug transport is mainly due to the overexpression of P-glycoprotein in the ABCB1 gene, which enhances excretion through gene amplification, variation or promoter alteration, leading to the pumping of taxus and PARP inhibitors out of the cells. Dysregulation of drug activation is manifested as insufficient reduction of platinum-based prodrugs and accelerated metabolism of paclitaxel by CYP3A4, which is influenced by variations in metabolic enzymes, concomitant medications, and the tumor microenvironment. Target alterations include upregulation of the tubulin subtype TUBB3, which reduces paclitaxel binding, and PARP1 mutations that weaken the efficacy of PARP inhibitors. Enhanced DNA damage repair rapidly eliminates platinum-DNA adions through high expression of nucleotide excision repair proteins (XPA, ERRCC1), while mismatch repair defects prevent apoptotic signal transduction. Apoptosis evasion is achieved through p53 inactivation, inhibition of the mitochondrial pathway by overexpression of Bcl-2/Bcl-XL and blocking of the caspase cascade by IAPs proteins. These mechanisms form a closed loop of drug resistance from injury repair to apoptosis inhibition, jointly leading to chemotherapy failure.