Bepotastine sensitizes ovarian cancer to PARP inhibitors through suppressing NF-κB-triggered SASP in cancer-associated fibroblasts

Therapy-induced senescence (TIS) is common in tumor cells treated with poly (ADP-ribose) polymerase inhibitors (PARPis), and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPi and contribute to consequential treatment failure remain unclear. We previously revealed that PARPi triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPi showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent CAFs displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPi in both homologous recombination-deficient (HRD) and proficient (HRP) ovarian Cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPi in 3D organotypic cultures and HRD-positive PDX models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian Cancer.