Abstract
Despite the promising activity of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) in many cancer types with defects in the DNA damage response the majority of the treated patients acquire PARPi resistance and succumb to their diseases. Consequently, there is an urgent need to identify the mechanisms of PARPi resistance. Here, we show that PARPi treatment promotes STAT3 activation in ovarian cancer cells, tumor-associated immune cells and fibroblasts, resulting in PARPi resistance and immunosuppression. Comparison of ovarian cancer patient-matched tumor biopsies before and after PARPi therapy revealed that STAT3 activity was significantly higher in tumor cells and tumor-associated immune cells and fibroblasts post PARPi treatment. Moreover, one-time PARPi treatment activated STAT3 both in tumor cells as well as diverse immune subsets and fibroblasts. PARPi-treated immune cells exhibited decreased expression of immunostimulatory interferon (IFN)-γ and Granzyme B while increasing immunosuppressive cytokine IL-10. Finally, we demonstrate that the acquisition of PARPi resistance in ovarian cancer cells was accompanied by increased STAT3 activity. Ablating STAT3 inhibited PARPi-resistant ovarian tumor cell growth and/or restored PARPi sensitivity. Therefore, our study has identified a critical mechanism intrinsic to PARPi that promotes resistance to PARPi and induces immunosuppression during PARPi treatment by activating STAT3 in tumor cells and tumor-associated immune cells/fibroblasts.
Highlights
In recent years, inhibitors of poly(ADP-ribose) polymerase (PARP) have emerged as a promising new therapeutic approach for ovarian cancer treatment, especially for high-grade ovarian carcinoma with mutations in the BRCA1 or BRCA2 tumor suppressor genes [1]
No statistically significant difference was observed in the tumor sample of patient #6, the p-Signal transducer and activator of transcription 3 (STAT3) level was already high before PARP inhibitors (PARPi) treatment
These findings suggest that PARPi treatment increases phosphorylation of STAT3 (p-STAT3) levels in the tumor cells in BRCA mutated ovarian patients
Summary
Inhibitors of poly(ADP-ribose) polymerase (PARP) have emerged as a promising new therapeutic approach for ovarian cancer treatment, especially for high-grade ovarian carcinoma with mutations in the BRCA1 or BRCA2 tumor suppressor genes [1]. PARP Inhibitor-Mediated STAT3 Activation normally repaired by homologous recombination (HR), causing apoptosis of the BRCA-deficient cancer cells [2, 3]. Four PARP inhibitors (PARPi), Olaparib, Rucaparib, Niraparib, and Talazoparib are FDA-approved for ovarian and breast cancer treatment, and their efficacy depends on BRCA and homologous recombination deficiency (HRD) status, platinum sensitivity, and prior lines of therapy [4]. Despite being one of the most promising new classes of cancer therapeutics, PARPi face enormous hurdles for ovarian cancer treatment. It is necessary to understand the primary and secondary resistance mechanisms to PARPi to improve patient treatment outcomes
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