416 Elucidating resistance mechanism to parp inhibitors for the development of novel therapeutic approaches in high-grade serous ovarian cancer

Introduction/BackgroundPARP inhibitors (PARPi) have been established as a targeted therapeutic approach not only in patients with high-grade serous ovarian cancer (HGSOC) that have genetic loss of function of BRCA1/2-associated DNA repair. However, treatment efficacy varies and neither BRCA mutation...

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Published inInternational journal of gynecological cancer Vol. 30; no. Suppl 4; p. A79
Main Authors Kulbe, Hagen, Kassuhn, Wanja, Ringel, Frauke, Welsch, Gabriele, Treffkorn, Peggy, Taube, Eliane, Horst, David, Sehouli, Jalid, Braicu, Elena
Format Journal Article
LanguageEnglish
Published Kidlington Elsevier Inc 01.12.2020
Elsevier Limited
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ISSN1048-891X
1525-1438
DOI10.1136/ijgc-2020-ESGO.133

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Summary:Introduction/BackgroundPARP inhibitors (PARPi) have been established as a targeted therapeutic approach not only in patients with high-grade serous ovarian cancer (HGSOC) that have genetic loss of function of BRCA1/2-associated DNA repair. However, treatment efficacy varies and neither BRCA mutation, nor homolog recombination deficiency (HRD) status seem to be optimal predictors. Moreover, mechanisms of treatment resistance are poorly understood and novel approaches are urgently required.MethodologyHere we created gene expression data of HGSOC patients (n=52) before PARPi treatment to elucidate key signaling pathways of resistance to increase their efficacy in combinatorial therapeutic strategies. We performed a comprehensive bioinformatics analysis of the differentially expressed genes between the 25% extreme responders (n=26; 13 each group), including gene set enrichment analysis (GSEA) and causal inference analysis with the CARNIVAL pipeline to elucidate the underlying molecular and regulatory mechanisms governing treatment efficacy and resistance.ResultsIn accordance with recent publications, we found higher levels of MYC activity in non-responders and deregulation of the Wnt/ß-catenin signaling pathway resulting in PARPi treatment resistance. The pathway enrichment analysis also revealed specific pathways especially PDGFR, FGFR, PI3K/mTOR and MAPK signaling pathway associated with resistant phenotype. Furthermore, we have identified key kinases, particularly JAK1/2 and SRC that might mediate resistance to PARP inhibition. In addition, differential gene expression analysis revealed folate receptor 1 (FOLR1) to be significantly higher expressed in non-responders (logFC = 2.66; p < 0.0026) with the potential as a serum-based biomarker not only for ovarian cancer, as it correlates closely with CA125, but also PARPi treatment efficacy.ConclusionIn conclusion, these findings define a network of pathways, that are crucial to mediate mechanism of PARPi resistance and identified key signaling kinases as therapeutic targets in ovarian cancer.DisclosuresThe authors declare no conflict of interest.
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ISSN:1048-891X
1525-1438
DOI:10.1136/ijgc-2020-ESGO.133