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| Home > Publications database > Strong Hsp90α/β Protein Expression in Advanced Primary CRC Indicates Short Survival and Predicts Response to the Hsp90α/β-Specific Inhibitor Pimitespib. |
| Home > Publications database > Strong Hsp90α/β Protein Expression in Advanced Primary CRC Indicates Short Survival and Predicts Response to the Hsp90α/β-Specific Inhibitor Pimitespib. |
| Journal Article | DKFZ-2025-01203 |
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2025
MDPI
Basel
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Please use a persistent id in citations: doi:10.3390/cells14110836
Abstract: The prognosis of advanced (UICC IIb-IV) primary colorectal cancer (pCRC) remains poor. More effective targeted therapies are needed. Heat shock protein 90 alpha/beta (Hsp90α/β) expression was immunohistologically quantified in 89 pCRCs and multivariately correlated with survival. Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was tested in pCRC cell lines and patient-derived cancer spheroids (PDCS) and referenced to the pan-Hsp90 inhibitor ganetespib (Gan, STA-9090) and standard-of-care therapies. A total of 26.97% pCRCs showed strong tumoral Hsp90α/β expression (Hsp90α/β > 40%), which correlated with reduced PFS (HR: 3.785, 95%CI: 1.578-9.078, p = 0.003) and OS (HR: 3.502, 95%CI: 1.292-9.494, p = 0.014). Co-expression of Hsp90α/β > 40% with its clients BRAF-V600E and Her2/neu aggravated the prognosis (BRAF-V600E mutated: PFS, p = 0.002; OS, p = 0.012; Her2/neu score3: PFS, p = 0.029). The prognostic cut-off Hsp90α/β > 40% was also a predictor for response to Pim-based therapy. Pim efficacy was increased in combination with 5-FU, 5-FU + oxaliplatin, and 5-FU + irinotecan (all p < 0.001). Pim induced sensitization to all chemotherapies in HT-29 (p < 0.001), Caco-2 (p < 0.01), and HCT116 (p < 0.05) cells. Pim combined with encorafenib in HT-29 and with trastuzumab in Caco-2 cells was most effective in dual-target inhibition approaches (HT-29: p < 0.005; Caco-2: p < 0.05). The anti-cancer effect and chemosensitization of Pim-based therapy were prospectively confirmed in PDCS directly generated from Hsp90α/β > 40% pCRCs. Protein profiling combined with functional drug testing stratifies Hsp90α/β > 40% pCRC patients diagnosed with UICC IIb-IV for effective Pim-based therapy.
Keyword(s): Humans (MeSH) ; HSP90 Heat-Shock Proteins: metabolism (MeSH) ; HSP90 Heat-Shock Proteins: antagonists & inhibitors (MeSH) ; Colorectal Neoplasms: drug therapy (MeSH) ; Colorectal Neoplasms: metabolism (MeSH) ; Colorectal Neoplasms: pathology (MeSH) ; Female (MeSH) ; Male (MeSH) ; Aged (MeSH) ; Middle Aged (MeSH) ; Cell Line, Tumor (MeSH) ; Prognosis (MeSH) ; Triazoles: pharmacology (MeSH) ; Triazoles: therapeutic use (MeSH) ; Spheroids, Cellular: drug effects (MeSH) ; Spheroids, Cellular: metabolism (MeSH) ; CRC ; Hsp90α/β ; TAS-116 ; chemosensitization ; ganetespib ; patient stratification ; patient-derived cancer spheroid model ; personalized therapy ; pimitespib ; prognosis ; HSP90 Heat-Shock Proteins ; STA 9090 ; Triazoles ; HSP90AB1 protein, human
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