Immunomodulatory Imide Drugs Disrupt the Endogenous Chaperone Function of CRBN in a Novel Mechanism of Action

Abstract

Immunomodulatory drugs (IMiDs), including thalidomide, pomalidomide, and lenalidomide, are essential therapeutics for multiple myeloma (MM) throughout the course of treatment. However, most patients with MM eventually develop IMiD resistance and relapsed/refractory MM. Although IMiDs are known to target Cereblon (CRBN), an E3 ubiquitin ligase substrate receptor, and induce neo-substrate degradation of critical MM proteins, the mechanisms of resistance development and IMiD action are not fully understood. Here, novel endogenous interactors of CRBN identified via the µMap proximity labeling platform reveal a novel mechanism of action of IMiDs in inhibiting native CRBN co-chaperone function with heat shock proteins (HSPs). Independently of induced neo-substrate degradation, IMiDs destabilize CRBN interactors in lenalidomide-sensitive MM lines and increase apoptotic markers. In contrast, CRBN’s stabilization of proteins and nascent protein synthesis is maintained in lenalidomide-resistant MM lines, which attenuate the IMiD-mediated destabilization effect by upregulating critical HSPs. Combination treatment with HSP inhibitors and IMiDs can leverage this mechanism to sensitize IMiD-resistant MM cells to IMiD treatment. These data establish a novel mechanism of action and nominate native CRBN interactors and chaperone function as therapeutic targets for next-generation MM therapeutics.