Bortezomib resistance and MUC1 in myeloma

Abstract

In this issue of Blood, Yin et al make the novel discovery that targeting the mucin 1 C-terminal subunit (MUC1-C) oncoprotein reverses resistance to the proteasome inhibitor bortezomib in multiple myeloma cells by triggering depletion of glutathione (GSH) pools and induction of oxidative injury. They also report that these events proceed through a process involving downregulation of the p53-inducible regulator of glycolysis and apoptosis (TIGAR). Specifically, the authors show that MM cells resistant to bortezomib display compensatory upregulation of TIGAR and GSH and that these responses are blocked by a pharmacologic inhibitor of MUC1-C (GO-203), resulting in a marked synergistic increase in reactive oxygen species (ROS) and cell death. One of the more interesting features of this study is that it touches on multiple concepts, including drug resistance, oncogene addiction, oncogenic stress, and inhibition of stress-related pathways in a manner that has very clear translational implications. © 2014 by The American Society of Hematology.