Abstract 2547: YAP1 associates with the EPHA3 receptor tyrosine kinase to promote prostate cancer progression

Abstract

Abstract Metastatic castration-resistant prostate cancer is lethal, and the mechanisms contributing to this deadly disease are largely unknown. The disparity in our knowledge poses a significant barrier to developing effective therapeutics against advanced prostate cancer in humans. Evidence suggests that the ephrin family of receptor tyrosine kinase signaling may play a critical role in the pathobiology of prostate cancer progression. However, the mechanism is elusive. Our initial study showed that YAP1, in concert with the TEAD1 transcription factor, regulated EPHA3 expression. However, the significance of EPHA3 signaling in prostate cancer remains elusive. Here we investigated the role of EPHA3 signaling in prostate cancer cells. We showed that the expression of EPHA3 correlated with YAP1 in prostate cancer clinical samples. We also showed that EPHA3 knockout reduced cell growth in 2D and 3D cultures. In addition, EPHA3 loss sensitized castration-resistant prostate cancer cells to enzalutamide. Moreover, EPHA3 knockout reduced the GTPase activity of RHOA compared to cells with EPHA3-WT, which coincided with reduced phospho-ERK1/2 levels. Consistently, EPHA3 knockout reduces phosphor-ERK1/2, similar to the inhibition of phospho-ERK1/2 by an inhibitor of ROCK1 (Rho-associated coiled-coil-containing protein kinase 1). Besides, EPHA3 knockout reduced the expression of EMT markers ZEB1/2 and the cancer stem cell marker CD44 compared to the wild type. Furthermore, the levels of EPAH3 transcripts were higher in high-grade PC of AA patients compared to other races. Finally, AA and Caucasian Americans (CA) PC cell lines differentially express the member of ephrin-A and ephrin-B receptors. These observations suggest that the YAP1-EPHA3 signaling is a viable therapeutic target for patients with advanced prostate cancer. Citation Format: Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Kezhan Khazaw, Bekir Cinar. YAP1 associates with the EPHA3 receptor tyrosine kinase to promote 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 2547.