Abstract 6803: RNF5-DNAJA1 axis dictates selinexor sensitivity of multiple myeloma by regulating mitochondrial function

Abstract Selinexor is a First-in-Class XPO1 Inhibitor approved for relapsed or refractory multiple myeloma (RRMM), but the overall response rate remains unsatisfactory. The main mechanism by which Selinexor kill MM cells is to suppress the export of tumor suppressor proteins and oncoprotein mRNAs, however other key underlying mechanisms need to be investigated. Here, using a proteomics of nucleocytoplasmic separation assay, we discover that a ring finger containing E3 ligase, RNF5, is a cargo substrate of XPO1 and its nuclear-cytoplasmic transport is correlated with poor clinical therapeutic response. In the interactome of XPO1, we identify that DNAJA1 is a new partner of RNF5 and catalyzes K29-linked polyubiquitination of DNAJA1, which strengthens the interaction between DNAJA1 and HSP70, consequently and antagonizes the interaction of HSP70 and HSF1, therefore activates UPRmt activation and mitochondrial protection. Thus, administration of RNF5 inhibitor inh-02 and DNAJA1 inhibitor 116-9e disrupts UPRmt balance and sensitizes selinexor in vitro culture cell lines and in the xenograft and Vk*Myc mouse models. Collectively, our study elucidates the machinery of XPO1-RNF5-DNAJA1 axis in regulating mitochondrial function, and sheds light on developing new strategies to improve the efficacy of treating RRMM patients. Citation Format: Mengqi Wang. RNF5-DNAJA1 axis dictates selinexor sensitivity of multiple myeloma by regulating mitochondrial function [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 6803.