Abstract 2625: KRAS activity-mediated mechanism of castration-resistant prostate cancer progression

Abstract

Abstract Purpose: Prostate cancer is highly androgen-dependent, and androgen receptor (AR) signaling is suppressed by treatment. However, there are cases in which disease progresses rapidly at the end of treatment even after AR suppression, suggesting that the disease progresses by mechanisms different from AR. The aim of this study is to investigate the KRAS signaling pathway as one of the mechanisms. Methods: We used the hormone-sensitive prostate cancer (HSPC) cell line LNCaP and the castration-resistant prostate cancer (CRPC) cell line DU145. We performed KRAS knockdown by si-RNA and activation of KRAS signaling by EGF stimulation. To examine KRAS signaling, PCR and Western blotting were performed. The changes in proliferation and migration due to inhibition and activation of KRAS signaling were confirmed. Results: RT-PCR showed a fusion gene of ubiquitin-conjugating enzyme UBE2L3 and KRAS (UBE2L3-KRAS) in DU145. Western blotting showed increased phosphorylation of ERK and p38 downstream of KRAS in DU145. KRAS knockdown inhibited proliferation and migration in DU145 but not in LNCaP. In EGF-stimulated activation of KRAS signaling, Western blotting showed activation of downstream KRAS signaling in LNCaP, but no change in proliferation and migration in fetal bovine serum (FBS)-added medium. In contrast, EGF stimulation of DU145 further activated downstream KRAS signaling and promoted proliferation and migration. The AR-dependent LNCaP showed almost no effect of KRAS signaling activation on cancer progression, whereas DU145 showed that KRAS signaling is involved in cancer progression. Conclusion: While HSPC is highly AR-dependent and does not show any effect of KRAS on cancer progression, KRAS may be involved in cancer progression in some CRPCs. Citation Format: Taiki Kamijima, Kouji Izumi, Yoshifumi Kadono, Atsushi Mizokami. KRAS activity-mediated mechanism of castration-resistant prostate cancer progression [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 2625.