Abstract 339: Mechanisms of resistance to poly (ADP-ribose) polymerase inhibitors in prostate cancer

Abstract

Abstract Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated promise in treating cancers with DNA damage repair (DDR) gene abnormalities. As a result, olaparib and more recently, rucaparib have been given Breakthrough Therapy designation by the FDA for use in metastatic castration resistant prostate cancer (mCRPC) with BRCA1/2 and ATM mutations. One of the problems encountered with PARPi is drug resistance which generally limits drug efficacy. Mechanistic studies on PARPi resistance have shown one of the main mechanisms of acquired resistance to be a reversion mutation of BRCA1/2. However, this is likely more applicable to cancers in which impaired BRCA1/2 function is due to a mutation rather than in prostate cancer (PC) where BRCA2 tends to be frequently deleted. Therefore, we hypothesize that mechanisms of resistance to PARPi in PC may involve alternative molecular mechanisms rather than a reversion mutation. Methods: We used human castration-resistant PC cell lines that harbor genomic deletions of BRCA2, PC-3 and LnCaP-Abl, and performed cell viability (MTT) assays to determine the inhibitory growth (IG) concentrations of these cell lines with talazoparib and olaparib. We cultured parental PC-3 cells in sublethal concentrations (IG 50% and IG 90%) of talazoparib-supplemented media to develop talazoparib-resistant cells. RNA sequencing followed by gene-set enrichment analysis (GSEA) of hallmark gene sets was performed on the talazoparib-resistant PC-3 cells to understand the underlying molecular mechanisms. Results: We observed that the talazoparib-resistant PC-3 cells exhibited significantly enhanced cell growth compared to parental cells when cultured in the IG 90% concentration of olaparib. However, interestingly, the talazoparib-resistant cells grew much slower in 2D compared to parental PC-3 cells when cultured in the PARPi-free media. Our transcriptomic analysis showed significant enrichment of various inflammatory response pathways, including TNF-α and IFNα/γ signaling pathways, in the talazoparib-resistant cells and even in the parental PC-3 cells transiently treated with talazoparib. Conclusion: We hypothesize that resistance to PARPi in PC may be related to upregulation of inflammatory signaling. Therefore, further exploration of TNF-α and IFNα/γ and their role in PARPi resistance mechanisms may lead to the identification of targets that allow for overcoming PARPi resistance in PC. Citation Format: Mohammad Atiq, Goutam Chakraborty, Subhiksha Nandakumar, Ying Z. Mazzu, Konrad Stopsack, Yuki Yoshikawa, Nabeela Khan, Gwo-Shu Mary Lee, Philip W. Kantoff. Mechanisms of resistance to poly (ADP-ribose) polymerase inhibitors in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 339.