C-terminal HSP90 inhibitor L80 elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition

Novel C‐terminal heat shock protein 90 inhibitors target breast cancer stem cells and block migration, self‐renewal, and epithelial–mesenchymal transition

“…Similar to our findings in vitro , we observed significant knockdown of CD44 in mice treated with KU711 and KU758 but not in mice treated with the N‐terminal HSP90 inhibitor 17‐AAG. Our results with C‐terminal HSP90 inhibitors are similar to the treatment of the TNBC cells with a deguelin derivative, L80, which showed targeting of TICs via STAT3 inhibition in TNBC cells (Cho et al , 2019). Further supporting the efficacy of KU711 and KU758 at targeting TICs is the demonstrated decrease in migration and invasion and protein levels of BMI‐1, EZH2, and vimentin, which are all implicated in metastasis and epithelial–mesenchymal transition.…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…Unlike N-terminal inhibitors, such as AUY922 and 17-AAG, these C-terminal inhibitors do not increase the expression of HSP27, HSP40, and HSP70, suggesting their efficacy in anti-cancer function [207]. In triple-negative breast cancer, the C-terminal HSP90 inhibitor L80 effectively reduces the cell proliferation, breast cancer stemness, tumor growth, and metastasis by inhibiting AKT/MEK/ERK/JAK2/STAT3 signaling, while not affecting normal cells [208]. GRP94-selective inhibitor 30 has been developed from the structural modification of the first generation cis-amide bioisostere imidazole to improve its affinity for GRP94 [209].…”

“…Gambogic acid-selective HSP90β inhibitor, inhibition of cell growth, induction of cell cycle arrest and apoptosis, sensitization of cancer cells to gemcitabine by regulating ERK/E2F1/RRM2 signaling pathway [203] Prostate cancer KU675-C-terminal HSP90 inhibitor, exhibition of anti-proliferative and cytotoxic activity by suppressing formation of HSP90 complexes and degrading client proteins [206] Prostate cancer SM253 and SM258-C-termincal HSP90 inhibitor, suppression of cell proliferation, induction of apoptosis, no effect on the expression of HSP27, HSP40, and HSP70 [207] Triple-negative breast cancer L80-C-terminal HSP90 inhibitor, reduction of cell proliferation, cancer stem cell like properties and metastasis by regulating AKT/MEK/ERK/JAK2/STAT3 signaling pathway [208] Lung and gastric cancer TAS-116-selective HSP90α and β inhibitor, reduction of multiple HSP90 clients, efficient anti-cancer activity [204,205] Breast and prostate cancer GRP94-selective inhibitor 30-GRP94 inhibitor, potent anti-cancer activity [209] 6.6. HSF1 Inhibition for Cancer Therapy…”

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…However, another HSP90α-involving mechanism was proposed for CSC-like cells in triple-negative breast cancer: HSP90α together with GRP78 interacts with the zinc finger motif-containing C-terminal region of RPDM14, which was associated with cancer cell stemness, whereas the prevention of those HSP90α-RPDM14 interactions by HSP90 inhibitors or GRP78 inhibitors led to a decrease in the CSC-like cell populations (CD24−/CD44+ and SP cells) [80]. In a more recent publication dedicated to triple-negative breast cancer [81], the inhibitor (L80)-sensitive HSP90 chaperone function was shown to be necessary for activation of the Akt/MEK/ERK/JAK2/STAT3 signaling network, which generated CSC-like cell phenotypes (CD44+/CD24− cells with high ALDH1 activity, which are able to form mammospheres). An involvement of HSP90α in TRPM7-dependent HSP90α/uPA/MMP2 signaling was associated with extracellular proteinase activity, expression of cancer stemness markers, multicell spheroid-forming ability, and high metastatic potential of lung CSC-like cells [82].…”

“…So, experimental ways to prevent or reverse EMT have been described for inhibitors of HSP90 activity, such as NVP-AUY922 [66], ganetespib [65,68], KU711, and KU757 [72]. In many research groups, the CSC-repressing and/or CSC-sensitizing effects of the inhibition of intracellular HSP90 activity were observed with geldanamycin [63,76], AR-42 (a histone deacetylase inhibitor) [87], emodin [75], 17AAG [73,74,[92][93][94], 17DMAG [79,80], NVP-AUY922 [92], WGA-TA [74], KU711 [72,74], Ku757 [72], L80 [81], and panaxynol [95]. In a system with in vitro and in vivo models, NVP-AUY922 has recently been used to inhibit the HSP90A-dependent TCL1A/Akt pathway, which confers stemness-like properties in immune-refractory tumors [27].…”