Activation of cGAS confers PARP inhibitor resistance in ovarian cancer via the TBK1-IRF3 axis.

Objectives: Ovarian cancer is a gynecologic tumor with the highest mortality rate worldwide. Nonetheless, chemoresistance remains a significant obstacle in treating ovarian cancer. PARP inhibitors (PARPis) are effective drugs approved for maintenance therapy in ovarian cancer. However, the development of natural or acquired resistance to PARPis poses a major challenge for ovarian cancer treatment.

Methods: Public database analysis of cGAS expression in relation to PARPi resistance. cCK-8 assay was used to determine cell survival. qPCR assay with Western Blot was implemented to determine gene expression and protein activation status.

Results: Analysis of public databases revealed significantly higher cGAS expression in Olaparib-resistant cells and in recurrent ovarian tumors. Furthermore, high cGAS expression significantly promoted Olaparib tolerance in ovarian cancer cells. Our findings demonstrate that Olaparib treatment induces activation of the TBK1-IRF3 signaling axis downstream of cGAS, leading to the production of type I interferon. This, in turn, activates NF-κB and IL-6-STAT3 signaling, contributing to inflammation and PARPi resistance. Consequently, targeting cGAS effectively counteracts Olaparib resistance and enhances its efficacy in suppressing cancer cell growth, ultimately leading to cell death.

Conclusions: Our study highlights the crucial function of cGAS signaling in mediating PARPi resistance in ovarian cancer cells. These findings provide valuable novel therapeutic strategies targeting cGAS to improve the efficacy of PARPi-based treatments for ovarian cancer.