Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer

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. What's new? A major challenge in pancreatic cancer is primary resistance to chemoradiotherapy. Although the mechanisms of resistance are multi‐faceted, client proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor‐1 α (HIF‐1α) play a central role. Here, the authors show that the HSP90 inhibitor ganetespib can down‐regulate HIF‐1α pathways in addition to survival and angiogenic pathways in pancreatic cancer cell lines resistant to chemoradiotherapy, resulting in their resensitization to treatment. These findings are important for elucidating mechanisms of resistance in pancreatic cancer and for developing clinically‐relevant strategies such as combination treatments to overcome chemoradioresistance.