Abstract 3904: Simvastatin intensifies anti-androgen efficacy against treatment-resistant prostate cancer cells
Authors: Siltari Aino , Korhonen Olga , Raittinen Paavo , Bläuer Merja , Syvälä Heimo , Tammela Teuvo L. , Murtola Teemu J. 
Published: April 2023

Abstract
Androgen receptor (AR) signaling inhibitors (ARSIs) bicalutamide (Bic) and enzalutamide (Enza) are used in the treatment of castration resistant prostate cancer (CRPC). Prostate cancer (PCa) cells eventually develop treatment resistance against these drugs causing clinical challenges. The mechanisms behind treatment resistance are complex and only partially known. Androgen signaling is linked to lipid and cholesterol metabolism, and they likely play a role in the development of treatment resistance. Cholesterol producing mevalonate pathway can be inhibited by statins, but it is unknown whether statin treatment could enhance effects of ARSIs. We studied combined effects of simvastatin (Sim) with or without Bic or Enza in VCaP originated PCa cell lines resistant to these ARSIs. Unique treatment resistant cell lines were created with long-term cultures of VCaP cells. The cells were kept under anti-androgen influence until the cells were growing normally despite the ARSIs. We analyzed changes in cell growth, RNA expression, and relevant AR signaling and cholesterol metabolism protein expression. Prostate-specific antigen (PSA) secretion was measured as a marker of AR signaling activity. In Bic or Enza resistant cell lines, combination of 2.5 or 5 μM simvastatin + 10 μM Bic/Enza decreased cell growth more than Sim alone, i.e., ARSIs demonstrated efficacy in combination therapy against ARSI resistant cells. In Bic and Enza resistant cells, combination treatment increased the expression of 60 and 26 and decreased the expression of 33 and 48 genes, respectively, compared with simvastatin alone. Altogether, 16 genes expression changed similarly in both cell lines in response to combination therapy. In both cell lines, over 70% of all gene changes were seen on AR-regulated genes. In Bic resistant cells, Sim decreased PSA levels with or without Bic. On the contrary, in Enza resistant cells PSA levels were increased with combination of Sim and Enza. We showed that combined treatment with ARSI and Sim inhibited cell growth more than Sim alone in ARSI resistant cell lines. This suggests that inhibition of the mevalonate pathway could enhance androgen signaling inhibition and potentially circumvent ARSI resistance mechanisms. This phenomenon is supported by epidemiological studies as patients treated with anti-androgens responded better during simultaneous statin treatment. Gene expression differed in combination treatment compared to Sim alone. Future studies are needed on whether interventions on lipid and cholesterol metabolism could enhance treatment of CRPC. Knowledge about the precise mechanisms behind the treatment responses and resistance might lead to new therapeutic applications.
Citation Format: Aino Siltari, Olga Korhonen, Paavo Raittinen, Merja Bläuer, Heimo Syvälä, Teuvo L. Tammela, Teemu J. Murtola. Simvastatin intensifies anti-androgen efficacy against treatment-resistant prostate cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3904.