Identifying Mechanisms Responsible for PARP Inhibitor Resistance in Ovarian Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of patients with high-grade serous ovarian cancer. However, treatment efficacy varies and neither BRCA mutation nor homologous recombination–deficiency status predict treatment response optimally. Researchers sought to better understand the molecular and regulatory mechanisms responsible for treatment efficacy and response.

Researchers created gene expression data of 52 patients with high-grade serous ovarian cancer to clarify the mechanism of PARP inhibitor resistance and identify key signaling kinases to target in the treatment of ovarian cancer. A comprehensive bioinformatics analysis was performed of the differentially expressed genes in 13 patients who were high responders to treatment and 13 nonresponders to elucidate the underlying molecular and regulatory mechanisms responsible for treatment efficacy and resistance.

Higher levels of MYC activity were found in patients identified as treatment nonresponders compared with high responders. Deregulation of the Wnt/β-catenin signaling pathway was also found in nonresponders. These patterns resulted in PARP inhibitor treatment resistance. Pathway enrichment analysis demonstrated specific pathways associated with a resistant phenotype, especially PDGFR, FGFR, PI3K/mTOR, and MAPK signaling pathway. The kinases JAK1/2 and SRC were identified as potential mediators in resistance to PARP inhibition. Differential gene expression analysis revealed that folate receptor 1 demonstrated significantly higher expression in nonresponders and may hold potential as a serum-based biomarker for ovarian cancer and for PARP inhibitor treatment efficacy.

Researchers identified a network of pathways crucial in the mechanism of PARP inhibitor resistance, including PDGFR, FGFR, PI3K/mTOR, and MAPK signaling pathway. In addition, the key signaling kinases JAK1/2 and SRC were identified as therapeutic targets in the treatment of ovarian cancer. Finally, folate receptor 1 may hold potential as a biomarker for PARP inhibitor treatment response.

Abstract 416. ESGO 2020.