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A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction...

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Detalles Bibliográficos
Autores principales: Kim, Ji Young, Cho, Tae-Min, Park, Jung Min, Park, Soeun, Park, Minsu, Nam, Kee Dal, Ko, Dongmi, Seo, Juyeon, Kim, Seongjae, Jung, Eunsun, Farrand, Lee, Nguyen, Cong-Truong, Hoang, Van-Hai, Thanh La, Minh, Ann, Jihyae, Nam, Gibeom, Park, Hyun-Ju, Lee, Jeewoo, Kim, Yoon-Jae, Seo, Jae Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166677/
https://www.ncbi.nlm.nih.gov/pubmed/35501463
http://dx.doi.org/10.1038/s41388-022-02269-y
Descripción
Sumario:Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.