Abstract 283: Combination treatment of PARP and SRC inhibitors in BRCA2 mutated prostate cancer

Background: Recently, poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) have shown promise in metastatic castration resistant prostate cancers (mCRPC) patients harboring DNA repair defects due to mutations of BRCA1/2 and ATM. Despite responses, resistance is common and treatment modalities for PARPi-resistant patients are limited. We hypothesized that combining PARPi with other agents in BRCA2 altered tumors would create synergy and greater response rate and durability. Methods: We established a transcriptomic profile associated with genomic deletion of BRCA2 (homozygous and heterozygous) using publicly available datasets from mCRPC patient tumors. To identify the significantly unregulated oncogenic signaling pathways associated with BRCA2 loss, we used gene-set enrichment analysis (GSEA). We also analyzed this transcriptomic profile by Toppgene suite to identify potential drug targets for BRCA2 deleted tumors. We used experimental human prostate cancer cell lines to validate our current observations from human clinical datasets and pathway analysis. Results: Our GSEA analysis showed significant enrichment of the SRC signaling pathway in BRCA2-altered tumors, and based on the Toppgene suite, we also identified dasatinib (pharmacological inhibitor of SRC) as a potential agent for BRCA2-deleted tumors. Similarly, we observed significant up regulation of SRC phosphorylation in human prostate cancer cells (LNCaP-abl and PC3M) that harbor genomic deletion of BRCA2. We performed cell growth assays in these BRCA2 deleted cells treated with PARPi (olaparib, talazoparib), and dasatinib alone or in combination and calculated drug synergy based on the Chou-Talay Method. PC3M and LNCaP-abl prostate cancer cell lines showed different sensitivities to olaparib and talazoparib. We used olaparib for PC3M and talazoparib for LNCaP-abl cells. Co-administration of the PARPi and SRCi showed significant synergy in both cell lines compared to either inhibitors alone. We will develop the rationale for combining PARPi and SRCi in CRPC patients who harbor defects of BRCA2 after completion of our study in xenograft models. Conclusion: Our study reveals the synergistic effect of PARPi and SRCi in prostate cancer cell lines. We believe this shows great potential for future clinical trials in patients with mCRPC harboring BRCA2 deletions. Citation Format: Nabeela Khan, Goutam Chakraborty, Subhiksha Nandakumar, Ying Z. Mazzu, Mohammad Atiq, Yuki Yoshikawa, Gwo-Shu Mary Lee, Philip Kantoff. Combination treatment of PARP and SRC inhibitors in BRCA2 mutated 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 283.