Enhancing PARP inhibitor efficacy in ovarian cancer: targeting the PI3K/AKT/mTOR pathway

Ovarian cancer remains one of the most lethal gynecologic malignancies, often marked by late-stage diagnosis and resistance to conventional therapies. Poly (ADP-ribose) polymerase (PARP) inhibitors have significantly advanced treatment, particularly in tumors with homologous recombination deficiencies, such as BRCA1/2 mutations. However, their clinical benefit is limited in homologous recombination-proficient or BRCA wild-type tumors, necessitating the development of combination strategies to broaden therapeutic efficacy. The PI3K/AKT/mTOR signaling cascade, a key regulator of cell survival, proliferation, and DNA damage response, is frequently dysregulated in ovarian cancer and has emerged as a critical modulator of PARP inhibitor sensitivity. This review comprehensively examines preclinical and clinical evidence supporting the rationale for co-targeting the PI3K/AKT/mTOR axis to enhance the antitumor effects of PARP inhibitors. Natural and synthetic inhibitors of this pathway, as well as advanced nanotechnology-based delivery systems, have shown potential in overcoming intrinsic and acquired resistance to PARP inhibition. Furthermore, emerging data from biomarker-driven clinical trials highlight the importance of molecular stratification in optimizing treatment outcomes. Integrating PI3K/AKT/mTOR inhibition with PARP blockade represents a promising strategy to expand the therapeutic reach of PARP inhibitors and improve clinical outcomes in ovarian cancer.