Proteostasis Disruption by MYC Amplifies Sensitivity to Hsp90 Inhibitors in Tumor Cells

Hsp90 is a molecular chaperone that plays a crucial role in the stabilization and activity of numerous client proteins, many of which are involved in oncogenic signaling pathways. Despite initial enthusiasm, clinical trials with Hsp90 inhibitors have largely failed to meet expectations, highlighting the need for a deeper understanding of predictive biomarkers and the genetic factors influencing therapeutic response. The precise mechanism underlying the selective antitumor effects of Hsp90 inhibitors remains unclear, whether it stems from specific mutations and unstable proteins or broader disruptions in protein homeostasis within tumors. Here, we demonstrate that the sensitivity of tumor cells to Hsp90 inhibition is significantly diminished when proteosynthesis is arrested. To explore whether increased proteosynthesis drives the antitumor activity of Hsp90 inhibitors, we employed the non-tumor RPE1 cell line, which exhibits low sensitivity to Hsp90 inhibition. By introducing an inducible MYC oncogene, we induced enhanced ribosomagenesis, elevated RNA concentration, and increased overall proteosynthesis, resulting in heightened sensitivity to Hsp90 inhibition and subsequent cell death. Stress levels, as indicated by HSF1 pathway activation and cellular impedance measurements, were markedly elevated following Hsp90 inhibition in MYC-induced cells. These findings suggest that the antitumor efficacy of Hsp90 inhibitors is closely linked to proteostasis alterations induced by heightened metabolism and protein synthesis. Our results underscore the potential for MYC or related pathways as critical determinants of Hsp90 inhibitor sensitivity, offering a new therapeutic avenue for tumors resistant to conventional treatments targeting proteosynthesis inhibition.