HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition under Hypoxia

As one of the most common malignancies worldwide, Hepatocellular carcinoma (HCC) has been treated by Sorafenib, which is the first approved target drug by FDA for advanced HCC. However, drug resistance is one of the obstacles to its application. As a typical characteristic of most solid tumors, hypoxia has become a key cause of resistance to chemotherapy and radiotherapy. It is important to elucidate the underlying mechanisms of Sorafenib resistance under hypoxia. In this study, the morphological changes of hepatocellular carcinoma cells were observed by Live Cell Imaging System and Transmission Electron Microscope; Sorafenib was found to induce Necroptosis in liver Cancer. Under hypoxia, the distribution of Necroptosis related proteins was changed, which contributed to Sorafenib resistance. HSP90α binds with the necrosome complex and promotes chaperone-mediated Autophagy (CMA) degradation, which leads Necroptosis blocking and results in Sorafenib resistance. The patient-derived tumor xenograft (PDX) model has been established to investigate the potential therapeutic strategies to overcome Sorafenib resistance. 17-AAG inhibited HSP90α and presented obvious reversal effects of Sorafenib resistance in vivo and in vitro. All the results emphasized that HSP90α plays a critical role in Sorafenib resistance under hypoxia and 17-AAG combined with Sorafenib is a promising therapy for hepatocellular carcinoma.