In vivo manipulation of the protein homeostasis network in rhabdomyosarcoma

Dysregulation of the proteostasis network is associated with various diseases including cancer. Previous studies have shown that inhibiting components of this network, such as HSP70 chaperones, can selectively induce cell death in rhabdomyosarcoma (RMS), a common pediatric soft tissue sarcoma. Here we show that inhibiting VCP, an ATPase involved in protein degradation, activates the unfolded protein response and induces apoptosis in RMS, with a preclinical p97 inhibitor showing promising anti-tumor activity in mouse models. The findings confirm the efficacy of targeting the proteostasis network in RMS and suggest that targeting compensatory network components might yield synergistic outcomes. RNA-seq libraries were generated from xenografts subcutaneously injected into the flanks of nu/nu mice treated with either 50 mg/kg CB-5083 or methylcellulose vehicle.