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

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.

Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

“…HSP90 functions as a chaperone protein for a number of client proteins critical for the growth and survival of cancer cells (37), and its elevated expression is correlated with poor prognosis in PDAC and in multiple other cancers (38). The link between HSP90 inhibition and suppression of PI3K/AKT/mTOR signaling has been previously reported in a number of solid and hematological malignancies, and our results support these findings (17,39,40).…”

The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach

“…Onalespib for example, has been found to sensitize malignant glioma cells to temozolomide. The HSP90 antagonist ganetespib, has recently been investigated for sensitizing effects in ovarian cancer and pancreatic cancer cells to chemotherapy 25 and radiochemotherapy 26 , respectively. The HSP90 antagonist NVP-AUY922 potentiated anti-cancer effects of a BCL-2 inhibitor in small cell lung cancer 27 and demonstrated synergy in combination with trastuzumab in breast cancer 28 .…”

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

“…The use of HSP90 inhibitor AUY922 with platin-based radiation has shown efficacy in synergistic killing of mutant head and neck squamous cell carcinoma (HNSCC) cells through chromosomal fragmentation [119]. HSP90 inhibitor, Ganetespib, has been identified as a radiosensitizer that works via modulation of HIF-1α, STAT3, and AKT-driven pathways in pancreatic ductal adenocarcinoma [133]. Also, Ganetespib significantly limits the cancer cell survival by inducing G2-M arrest and disrupting DDR during irradiation [134].…”