# Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma

## TL;DR

A drug called omaveloxolone was found to block a key cellular process in multiple myeloma, leading to cancer cell death, even in drug-resistant cases.

## Contribution

Omaveloxolone is identified as a novel ERAD inhibitor with cytotoxic effects on multiple myeloma cells, including proteasome inhibitor-resistant ones.

## Key findings

- Omaveloxolone selectively inhibits ERAD degradation of ER luminal and membrane substrates.
- ERAD inhibition triggers apoptosis via altered lipid raft organization and activation of the extrinsic apoptotic pathway.
- Omaveloxolone shows in vivo anti-myeloma activity and is cytotoxic to primary malignant plasma cells.

## Abstract

Multiple myeloma (MM) is an incurable plasma cell neoplasm that is highly reliant on endoplasmic reticulum-associated degradation (ERAD) to maintain protein homeostasis. Disrupting ERAD has been proposed as a therapeutic strategy to overcome proteasome inhibitor resistance; however, the identification of novel inhibitors has been limited. To address this, we conducted a cell-based high-throughput screen using the FDA repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates, without affecting the degradation of key cytosolic proteins that are implicated in disease relapse. Surprisingly, although ER stress response pathways are activated after ERAD inhibition in MM, we find that apoptosis is mediated by altered lipid raft organization, leading to aberrant activation of the death-inducing signaling complex (DISC) and caspase 8 in the extrinsic apoptotic pathway. Notably, ERAD inhibition by RTA408 is cytotoxic to primary malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish a novel ERAD inhibitor, which is a valuable tool to dissect ERAD biology, and provide pre-clinical evidence for RTA408 as a therapeutic agent in MM.