C‑terminal HSP90 inhibitor NCT‑58 impairs the cancer stem‑like phenotype and enhances chemotherapy efficacy in TNBC

Treatment options for triple‑negative breast cancer (TNBC) are limited because they typically harbor a high cancer stem‑like population and exhibit a relatively aggressive metastatic phenotype. Heat shock protein 90 (HSP90), a molecular chaperone that regulates diverse oncogenic client proteins, has emerged as a compelling therapeutic target owing to its involvement in key tumor‑promoting processes, such as uncontrolled proliferation, angiogenesis and metastasis. Owing to the undesirable induction of a compensatory heat shock response (HSR) and systemic toxicity, classical N‑terminal inhibitors of HSP90 have failed in clinical trials. The impact of a rationally designed novel inhibitor of the HSP90 C‑terminus in TNBC cells was investigated. NCT‑58 eliminates rapidly proliferating tumor cells accompanied by simultaneous degradation of AKT, MEK and STAT3, and effectively eradicates the cancer stem‑like population (breast cancer stem cells) in both human MDA‑MB‑231 and murine 4T1 cells. The latter phenomenon is accompanied by reductions in the activity of ALDH1 and the CD44high/CD24low stem‑like population, as well as impairment of mammosphere formation. Furthermore, NCT‑58 markedly impairs cell migration, coinciding with the collapse of HSP90 client cytoskeletal proteins, including vimentin and F‑actin, in MDA‑MB‑231 cells in vitro. A synergistic effect was observed when NCT‑58 was combined with paclitaxel or doxorubicin in MDA‑MB‑231 cells. Collectively, these findings indicated that targeting the C‑terminal domain of HSP90 with NCT‑58 is a promising therapeutic strategy for the treatment of molecularly heterogeneous TNBC.