PI3K/AKT inhibition creates a synthetic lethal dependency on integrin αV-FAK signaling in ovarian cancer

ABSTRACT: The phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently altered in epithelial ovarian cancer, yet no pathway inhibitor is approved for this disease, reflecting modest single-agent efficacy and dose-limiting toxicity. To identify combination strategies, we performed a genome-wide CRISPR/Cas9 synthetic lethality screen using PI3K and AKT inhibitors as anchor perturbations. This unbiased approach identified integrin αV (ITGAV)-focal adhesion kinase (FAK; PTK2) signaling as a selective vulnerability arising under PI3K/AKT pathway inhibition. Analyses across ovarian and pan-cancer dependency datasets showed that integrin αV dependency tracks with PI3K/AKT pathway activation rather than with ITGAV expression. Genetic or pharmacologic disruption of integrin αV-FAK signaling synergized with PI3K or AKT inhibitors, reducing viability below baseline across ovarian cancer cell lines, patient-derived organoids, and xenograft models, and this synergy occurred irrespective of canonical PI3K pathway genomic alterations. Mechanistically, co-inhibition induced replication stress associated with accumulation of DNA-RNA hybrids (R-loops), leading to DNA damage and apoptotic cell death; expression of RNase H1, but not a catalytically inactive mutant, attenuated these effects, supporting a functional role for transcription-replication conflict. Combination treatment additionally impaired RAD51 loading in a PI3K-selective manner, suggesting that reduced homologous recombination capacity amplifies R-loop-derived damage. This response was not universal, and we define a transcriptional signature associated with replication stress that may support patient selection. Together, these findings establish integrin αV-FAK signaling as a conditional vulnerability of PI3K/AKT-inhibited ovarian cancer and provide a mechanistic rationale for co-targeting these pathways with clinically available agents.

ORGANISM(S): Homo sapiens

PROVIDER: GSE354224 | GEO | 2026/11/13

REPOSITORIES: GEO