Abstract 2460: Oncogenic regulation of lipogenesis in docetaxel resistant prostate cancer cells

Abstract

Abstract Prostate cancer is the second leading cause of cancer related deaths in men in the United States. Docetaxel is the standard chemotherapeutic agent available for patients with advanced prostate cancer, in both hormone sensitive and castration resistant settings. However, the development of resistance to docetaxel curtails the efficacy of the drug in prostate cancer patients. Aberrant lipid metabolism has been linked to poor outcomes and therapy resistance in prostate cancer, particularly through overexpression and activation of lipogenic enzymes including ATP citrate lyase, acetyl coA carboxylase, fatty acid synthase, and stearoyl coA desaturase. Together, these enzymes drive fatty acid biogenesis, which has been linked to docetaxel resistance. The purpose of this study is to delineate the molecular mechanisms underlying the lipogenic reprogramming of docetaxel resistant prostate cancer cells, as these represent targets for reversal of this drug resistance. Docetaxel resistant sublines of LNCaP, 22rv1, PC3 and DU145 cell lines were established through chronic continuous exposure to incrementally increasing concentrations of docetaxel, followed by authentication by single tandem repeat (STR) analysis and validation of resistance using MTT viability assays and immunoblot detection of multidrug resistance protein 1 (MDR1/p glycoprotein/ABCB1). Enhanced intracellular accumulation of lipids using BODIPY 493/593 staining and flow cytometric detection was used to confirm the lipogenic phenotype of docetaxel-resistant cells. Oncogenic cMYC expression was also detected by immunoblotting, and its role in regulating lipogenic enzyme expression was evaluated by siRNA interference in docetaxel resistant prostate cancer sublines. cMYC knockdown suppressed the expression of lipogenic enzymes including acetyl coA carboxylase, fatty acid synthase, and stearoyl CoA desaturase in docetaxel-resistant prostate cancer cells. Furthermore, pharmacological inhibition of cMYC production (JQ1) or activity (10058-F4) effectively resensitized resistant cells to docetaxel, as did targeting of key lipogenic enzymes. These data indicate that a cMYC associated lipogenic program is associated with docetaxel resistance in prostate cancer and may represent targets for interventions to enhance docetaxel response in patients with advanced prostate cancer. Citation Format: Shannalee R. Martinez, Adrián Pérez Aybar, Carlos J. Díaz Osterman. Oncogenic regulation of lipogenesis in docetaxel resistant prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2460.