Abstract 393: Targeting MCT inhibition to overcome enzalutamide resistance in prostate cancer

Abstract Prostate cancers (PCa) exhibit a unique metabolic profile with reliance on different forms of glucose metabolism at different stages of disease progression. Early stage PCa cells use the more efficient TCA cycle, while metastatic PCa cells switch to glycolysis (Warburg effect), leading to the accumulation of lactate. Lactate is exported out of the cells by monocarboxylate transporters (MCTs) to maintain redox balance. Such metabolic reprogramming can lead to gain-of-function mutations and affect drug sensitivity. Enzalutamide is a second-generation antiandrogen used for the treatment of metastatic castration-resistant PCa. However, resistance to Enzalutamide develops in most patients within 9-15 months. Since Warburg effect is a hallmark of metastatic PCa, we sought to understand whether lactate transport has any effect on Enzalutamide-resistance in PCa. We measured the expression of MCTs in parental and Enzalutamide-resistant C4-2B and 22RV1 cells and found that they are overexpressed in the Enzalutamide resistant subtypes. Based on this observation, we hypothesized that targeting lactate transport might be a potential strategy to overcome Enzalutamide-resistance in PCa cells. Using cell survival and cell proliferation assays, we found that MCT antagonists resensitized Enzalutamide resistant C4-2B and 22Rv1 cells to treatment with Enzalutamide. Using the Seahorse based glycolytic rate assay we found that these combination treatments significantly reduced the extracellular acidification rate by reducing the level of glycolysis in the Enzalutamide-resistant PCa cells. We also found that treatment with these antagonists either singly, or in combination with Enzalutamide suppressed xenograft growth in SCID mice bearing subcutaneously injected parental or Enzalutamide-resistant C4-2B cells. These findings led to the conclusion that targeting MCTs could be an attractive strategy to overcome Enzalutamide resistance in prostate cancer. Citation Format: Sayani Bhattacharjee, Jonathan P. Doan, Rebecca Wynn, Nagalakshmi Nadiminty. Targeting MCT inhibition to overcome enzalutamide resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 393.