A novel C-terminal HSP90 inhibitor NCT-58 targets cancer stem-like properties and suppresses migratory ability in triple-negative breast cancer cells

초록

Background: Although several N-terminal HSP90 inhibitors have been investigated in clinical trials, none have yet been approved for clinical use due to issues including induction of the heat shock response (HSR), off-target effects and toxicity. A major issue for N-terminal inhibitors is induction of the heat shock response (HSR) which triggers cell survival. In the present study, we investigated the effects of NCT-58, a rationally-designed novel HSP90 inhibitor that instead targets the C-terminal domain, and evaluated its capacity to induce apoptosis and target cancer stem-like properties in triple-negative breast cancer. Materials and Methods: The effect of NCT-58 on TNBC cell lines in vitro was evaluated with cell viability, apoptosis, heat shock response and cell migration. Cancer stem-like properties were examined by Aldefluor positivity, CD44+/CD24- stem-like population and mammosphere formation assays. Results: NCT-58 induces apoptosis in TNBC cells without triggering the heat shock response (HSR) due to its targeting of the C-terminal region. This is accompanied by potent and simultaneous degradation of AKT, MEK and STAT3. Importantly, NCT-58 kills not only the rapidly proliferating tumor cells and but also effectively eradicates the breast cancer stem-like population (BCSCs). The latter phenomena are accompanied by reductions in the activity of stem/progenitor marker ALDH1 and the CD44+/CD24- stem-like population and as well as impairment of mammosphere formation. Furthermore, NCT-58 markedly impairs cell migratory ability, coinciding with collapse of HSP90 client cytoskeletal proteins including vimentin and F-actin in TNBC cells in vitro. It is noteworthy that NCT-58 exhibits more cytotoxic to tumor cells but minimally cytotoxicity to non-malignant cells. Conclusion: These findings suggest that NCT-58 may represent an effective therapeutic approach for the simultaneous targeting of HSP90 and its client oncoproteins for the treatment of molecularly heterogeneous TNBC.