Abstract 4171: ADRM1 inhibitor, Up284 induces replication stress and suppresses cell proliferation in triple-negative breast cancer

Abstract Triple-negative breast cancer stands as the most aggressive and deadliest subtype of breast cancer associated with poor prognosis and limited treatment options due to the lack of important receptors; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) used for targeted therapy. Relying exclusively on chemotherapy enhances the chances of resistance and recurrence and leaves TNBC challenging to treat. Thus, it mandates the need for novel drug compounds and combination therapies. Adhesion-regulating molecule 1 (ADRM1/RPN13), a ubiquitin receptor of 26S proteasome that supports recognition of polyubiquitinated substrates and their subsequent deubiquitination and degradation by unique deubiquitinase UCH37/UCHL5.Its inhibition causes a rapid and toxic accumulation of its substrate polyubiquitinated proteins in very high molecular weight (HMW) aggregate; disrupting the protein homeostasis. In response to that, the cancer cells halt the cell cycle and induce replication stress. Consequently, cells signal the survival mechanism by signaling the DNA damage repair (DDR) pathway activation. Using the Cancer Gene Genome Atlas and GEO datasets, our primary analysis demonstrated that ADRM1 is overexpressed in all types of breast cancer including TNBC. Higher expression in tumor cells compared to normal cells strengthens the stands for ADRM1 as a potent target for therapy. In vitro analysis has been performed in TNBC cell lines MDAMB 453 and MDAMB 231. The dose dependency assay demonstrated that the UP284 compound showed activation of CHK1 (Checkpoint kinase1) mediated DNA damage response and γH2AX foci formation confirms the double-stranded DNA breakage. Clonogenic assay confirms the suppression of cell proliferation and colony formation in a concentration-dependent manner in both BRCA positive and BRCA mutant cell lines. Up284 treated cells also showed cell cycle arrest at the G2/M phase. Together, our results indicate that ADRM1 is a promising target for TNBC therapy and suggest that this ADRM1 inhibitor, Up284, has the potential for clinical application in the treatment of TNBC. Our analysis will unravel the novel mechanistic insight into the therapeutic potential of this compound and provide preclinical evidence to develop further combination therapy. Citation Format: Iffat Jahan, Shacoya Mack, Ravi Anchoori, Balasubramanyam Karanam, Komaraiah Palle. ADRM1 inhibitor, Up284 induces replication stress and suppresses cell proliferation in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4171.