Selinexor is a first-in-class XPO1 inhibitor approved for the treatment of relapsed or refractory multiple myeloma (RRMM). However, its overall response remains limited, suggesting that additional mechanisms underlying Selinexor sensitivity require further investigation. Nucleus-cytoplasm fractionation-based proteomic analysis is used to identify XPO1-transported proteins under Selinexor treatment. Protein-protein interactome and ubiquitination assays, mitochondrial function assessments, and the combined anti-tumor effects of specific inhibitors in vivo and in vitro are employed to define the regulatory machinery of the protein of interest in Selinexor sensitivity. The RING finger-containing E3 ligase, RNF5, is a cargo of XPO1 and its nuclear-cytoplasmic transport is correlated with poor clinical therapeutic response. RNF5 catalyzes K29-linked polyubiquitination of DNAJA1, which strengthens the interaction between DNAJA1 and HSP70, and consequently antagonizes the interaction between HSP70 and HSF1, therefore activates mitochondrial unfolded pprotein response (UPRmt) pathway to protect mitochondria function and MM survival. Thus, administration of RNF5 inhibitor inh-02 and DNAJA1 inhibitor 116-9e disrupts UPRmt balance and sensitizes MM cells to Selinexor. Our study elucidates the mechanism of the XPO1-RNF5-DNAJA1 axis in regulating sensitivity of Selinexor, and sheds light on developing new strategies to improve the efficacy of treating RRMM patients.
Wang et al. (Fri,) studied this question.