Abstract C043: Aberrant mRNA splice variants as novel prognostic biomarkers for tumor aggressiveness and treatment resistance in African American prostate cancer

Abstract

African Americans (AAs) have among the highest incidence of prostate cancer (PCa) and mortality attributable to this disease, and AA PCa disparities remains a clinical challenge. Specifically, AAs are 1.6 times more likely to develop PCa, and 2.4 times more likely to die from this disease compared to European Americans (EAs). A number of studies have shown that higher mortality and recurrence rates of PCa in AA men were observed even after adjustment for socioeconomic factors, suggesting that intrinsic biological difference may account for part of the PCa disparities. Our recent genomic study has identified global splicing events as critical drivers for promoting AA and EA PCa disparities. In this study, we utilized population-specific cell lines as in-vitro AA and EA PCa models to evaluate the molecular functions of the aberrant splice variants involved in cancer aggressiveness and drug resistance. Comprehensive functional assays (such as MTT, apoptosis, invasion, kinase activity assays, and western blotting analysis in PCa cells treated with vehicle or small molecule drugs, etc.) were employed to elucidate the functional roles of an oncogenic splice variant, PIK3CD-S, in AA and EA PCa cells in response to drug treatments. Immunohistochemistry and RNAScope assays were performed to examine the expression profile of PIK3CD-L (full length) and PIK3CD-S variants in an independent PCa cohort derived from AA and EA patients. Higher PIK3CD-S/PIK3CD-L expression ratios were detected in AA PCa cell lines and patient specimens. In addition, the functional validations have indicated that the higher PIK3CD-S/PIK3CD-L expression ratio in AA PCa cells potentially contributes to the higher cell proliferative and invasive capacities. By targeting splicing mechanism and/or PI3K isoforms using specific small molecule inhibitors in AA and EA cell models, we further explored the functional mechanisms of these oncogenic splice variants underlying the drug resistance. In conclusion, our molecular mapping/validation and functional analysis suggest that high PIK3CD-S/PIK3CD-L expression profile may contribute to the PCa aggressiveness and treatment resistance in AA PCa, potentially serving as a precision prognostic biomarker and novel drug target in advanced PCa Citation Format: Siyoung Ha, Himali Gujrati, Bi-Dar Wang. Aberrant mRNA splice variants as novel prognostic biomarkers for tumor aggressiveness and treatment resistance in African American prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C043.