Abstract 4868: Targeting of ERG positive prostate cancers with ERGi-USU-6 salt derivative

Abstract

Abstract Introduction: Prostate cancer (PCa) is the second leading cause of cancer deaths among men in the United States. Approximately 50% of patients with PCa harbor an oncogenic TMPRRS2- ERG gene fusion in their primary tumor and 35% of patients with metastatic castration resistant prostate cancers have the gene fusion. We have identified a potent small molecule inhibitor, ERGi-USU-6 salt derivative 7b, that selectively inhibits the growth of ERG positive tumor. This small molecule inhibitor is also effective in inhibiting the growth of benign and cancerous mouse prostate organoids expressing TMPRSS2-ERG (ERG positive organoids). To gain insights into the cancer-selective properties of ERGi-USU-6 salt 7b we evaluated pathways associated in ERGi-USU induced inhibition. Methods: The biological activities of salt derivative 7b, were assessed in hormone- refractory metastatic tumor derived ERG positive prostate cancer cell line, VCaP along with organoids. We monitored the pathways associated in the mechanism of drug action through, cell cycle-regulator proteins by immunoblot assays, cell cycle and ferroptosis related analyses in response to 7b treatment. We also monitored the levels of the RIOK2 kinase, previously shown to bind the parental ERGi-USU compound. The normal primary endothelium derived HUVEC cells were used as normal control due to the normal endogenous expression of ERG in endothelial cells including HUVEC. Results: Cell growth and immunoblot analysis indicated the inhibition of ERG positive prostate organoid upon ERGi-USU treatments resulting in the downregulation of ERG and RIOK2 protein levels. The cell cycle analyses, pathway mapping by protein assessment and ferroptotic assays suggests that salt derivative 7b treatment inhibits the ERG positive prostate cancer through ferroptosis along with RIOK2 inhibition. Conclusions: Our results showed that the ferroptosis inducer ATF3 gene is involved in the cancer-selective activity of ERGi-USU-6 salt derivative 7b. Further, based on our observations we hypothesize that ferroptosis, the iron-dependent form of programmed cell-death, may be the mechanism of cancer selective activity of salt derivative 7b. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Binil Eldhose, Katherine Beck, Cyrus Eghtedari, Gartrell C. Bowling, Mallesh Pandrala, Sanjay V. Malhotra, Xiaofeng A. Su, Albert Dobi. Targeting of ERG positive prostate cancers with ERGi-USU-6 salt derivative. [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 4868.