Abstract

Targeted protein degradation (TPD) approaches, including molecular glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs), overcome traditional occupancy-based inhibitor limitations and facilitate therapeutic development against “undruggable” disease-causing proteins. However, resistance to TPD is common, highlighting the need to further understand the driving mechanisms to improve treatment efficacy. Here, we identified a critical role of mTOR signaling in regulating PROTAC and MGD efficacy in vitro and in vivo. Activation or inhibition of mTOR respectively diminished or enhanced degradation efficacy of all proteasome-dependent TPD modalities tested. Mechanistically, mTOR inhibition suppressed de novo protein synthesis, thus creating a synthetic vulnerability by depleting replenishment of proteins targeted by PROTACs or MGDs. When applied to myeloma, mTOR inhibitors restored sensitivity to pomalidomide, one of the best characterized MGDs, in resistant cell lines and reduced malignant plasma cells in relapsed/refractory patients. This study reveals a clinically translatable strategy combining approved mTOR inhibitors with MGDs or PROTACs to enhance the therapeutic index of targeted protein degradation.