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• W2915678210 abstract "Resistance of pancreatic ductal adenocarcinoma (PDAC) to radiotherapy and chemotherapy represents a significant clinical issue. Although the mechanisms of resistance are multi-faceted, client proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor-1α (HIF-1α) have a central role in this process. The purpose of this investigation was to evaluate inhibition of HSP90 as a therapeutic strategy for radiosensitization in pancreatic cancer. Ganetespib, a selective inhibitor of HSP90, was evaluated as a radio-sensitizer in setting of PDAC. Inhibition of HSP90 by ganetespib potentiated the ability of radiation therapy to limit cell proliferation and colony formation in vitro. HIF-1α expression was upregulated by irradiation and HIF-1α-overexpressing stable cell lines were resistant to radiation. Inhibition of HSP90 with ganetespib reversed the effects of HIF-1α overexpression, by reducing signaling via proliferative, angiogenic and anti-apoptotic pathways. The potentiation of the antitumor effects of chemoradiotherapy by ganetespib and modulation of key pathways (e.g. HIF-1α, STAT3, and AKT) was confirmed in vivo in nude mice bearing HPAC xenograft tumors. These novel data highlight HIF-1α-mediated mechanisms of HSP90 inhibition that sensitize PDAC cells to chemoradiotherapy. This pathway and its pleiotropic effects warrant further evaluation in concert with conventional therapy in pancreatic cancer clinical trials." @default.
• W2915678210 created "2019-03-02" @default.
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• W2915678210 date "2019-03-19" @default.
• W2915678210 modified "2023-10-17" @default.
• W2915678210 title "Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer" @default.
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• W2915678210 doi "https://doi.org/10.1002/ijc.32227" @default.
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• W2915678210 hasPublicationYear "2019" @default.
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