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

초록

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.

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