Abstract 773: Inhibition of ubiquitin receptor ADRM1 for the treatment of metastatic breast cancer

Abstract

Abstract Adhesion-regulating molecule 1 (ADRM1) is a polyubiquitin receptor on the 26S proteasome. ADRM1 is upregulated in many cancers. In this study, we evaluated the potential prognostic and predictive value of ADRM1 in breast cancer patients. We determined the expression of ADRM1 and its relationship to breast cancer subtypes, using the Cancer Genome Atlas dataset that contained racial and clinical outcomes data totaling 1108 patients. The ADRM1 mRNA expression levels were divided into quartiles to designate the ADRM1 high versus low expression designation. Karanam et. al developed an orally available proteasome inhibitor bis-benzylidine piperidone (RA190), that binds to the ubiquitin receptor RPN13/ADRM1 on the 19S regulatory particle of the proteasome and directly kills cancer cells by triggering proteotoxic stress. RA190 binds to cysteine 88 of ADRM1/RPN13, triggering rapid accumulation of high-molecular-weight poly-ubiquitinated proteins resulting in apoptosis. Up284 is one of a second generation of small molecules that mimic RA190 activity. The objective of this study is to verify the role of ubiquitin receptor RPN13/ADRM1 in metastatic breast cancer samples of European American and African American patients and identify the safe combination of regimens of bortezomib in combination with Up289 to mitigate recurrence, metastasis and reduce mortality in AA TNBC/QNBC. Clinically, this will reveal a new, hitherto unknown targeted regimen for AA QNBC. From the biological perspective, it will provide insights into the underlying molecular changes that are associated with health disparities. Currently available treatments are unable to eradicate metastatic breast cancer specifically those classified as QNBC. Our preliminary analysis of Cancer Genome Atlas (TCGA) indicated that ADRM1 expression is highly expressed in AA versus EA breast cancer patients, resulting in a worse overall survival. Further analysis of ADRM1 in QNBC patients indicated that it was significantly elevated predominantly in African American patients with QNBC. Citation Format: Christopher Andrews, Clayton Yates, Balasubramanyam Karanam. Inhibition of ubiquitin receptor ADRM1 for the treatment of metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 773.