Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA.
Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA.
Int J Cancer. 2019 Sep 15;145(6):1529-1537. doi: 10.1002/ijc.32227. Epub 2019 Mar 19.
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.
胰腺导管腺癌 (PDAC) 对放疗和化疗的耐药性是一个重大的临床问题。尽管耐药机制具有多面性，但热休克蛋白 90 (HSP90) 的客户蛋白，如缺氧诱导因子-1α (HIF-1α)，在这个过程中起着核心作用。本研究旨在评估抑制 HSP90 作为胰腺癌放射增敏的治疗策略。HSP90 的选择性抑制剂Ganetespib 被评估为 PDAC 的放射增敏剂。Ganetespib 抑制 HSP90 增强了放疗限制体外细胞增殖和集落形成的能力。辐射诱导了 HIF-1α 的表达，而过表达 HIF-1α 的稳定细胞系对辐射具有抗性。Ganetespib 抑制 HSP90 逆转了 HIF-1α 过表达的作用，通过减少增殖、血管生成和抗凋亡途径的信号转导。Ganetespib 增强了放化疗的抗肿瘤作用，并在携带 HPAC 异种移植肿瘤的裸鼠体内证实了对关键途径（如 HIF-1α、STAT3 和 AKT）的调节。这些新数据强调了 HSP90 抑制的 HIF-1α 介导的机制，使 PDAC 细胞对放化疗敏感。该途径及其多效性作用值得在胰腺癌临床试验中与常规治疗一起进一步评估。
