Abstract 2330: MCT inhibition as a therapeutic strategy to target Enzalutamide-resistant prostate cancer

Abstract

Abstract Sayani Bhattacharjee, Jonathan Doan, Rebecca Wynn, Nagalakshmi Nadiminty Enzalutamide is a second-generation anti-androgen used for the treatment of prostate cancer. However, almost all patients develop resistance to this drug, thereby creating an urgent need of identifying new approaches that can overcome said resistance. Using parental and Enzalutamide-resistant C4-2B and 22RV1 cells, we targeted cellular metabolism to beat therapeutic resistance. Prostate cancers are more heterogeneous in their use of energy sources compared with other solid tumors and the most common metabolic end product is lactate, which is toxic to cancer cells upon accumulation. Hence, cancer cells upregulate the expression of monocarboxylate transporters (MCTs) that play a pivotal role in lactate efflux. Different MCT isoforms are differentially expressed across prostate cancer progression and presumably according to cellular demands at different stages. Gradual progression from benign prostate, to prostatic intraepithelial neoplasia, to in-situ carcinoma showed an increase in the expression of MCT2 and MCT4, with MCT4 being expressed in invasive prostate cancers. Based on our preliminary data that the expression of MCTs is higher in prostate cancer cells resistant to enzalutamide, we hypothesized that MCT inhibition may be an attractive therapeutic strategy against enzalutamide-resistant prostate cancer cells. Using cell survival, cell proliferation and clonogenic-ability assays, we found that the suppression of MCT activity using the MCT1/2 antagonists AR-C155858 or AZD3965 and the MCT 4 antagonist Syrosingopine not only diminishes the proliferation and survival of prostate cancer cells, but also re-sensitizes resistant cells to treatment with enzalutamide. We also found that treatment with AR-C155858 or AZD3965 either singly, or in combination with Enzalutamide suppressed prostate cancer cell xenograft growth in SCID mice bearing subcutaneously injected parental or Enzalutamide-resistant C4-2B cells. These findings imply that the MCTs have an intrinsic role in the acquisition of resistance to therapy. Citation Format: MCT inhibition as a therapeutic strategy to target Enzalutamide-resistant prostate cancer [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 2330.