Fudan University, Shanghai, China.
Title: Autophagy Protected Non-Small-Cell Lung Cancer from Vismodegib Treatment via Restricting the ROS
Biography: Dianwen Ju
Hedgehog (Hh) signaling pathway is evolutionary conserved and acts as a key player in early embryonic development. Hh is largely activated in most of tumors like non-small-cell lung cancers (NSCLCs) and regarded as a potential target for NSCLC therapy. Abnormally, treatment of Vismodegib, an Hh inhibitor, failed to exhibit a positive outcome in NSCLCs due to the unclear mechanisms. In this study, we reported the critical role of autophagy in the therapy-resistance in NSCLCs under the treatment of Vismodegib. We found that inhibition of Hh pathway by Vismodegib showed limited effect on the growth of NSCLC cells. At this period, autophagy and autophagic flux were triggered after Vismodegib treatment, while inhibition of autophagy sensitized the NSCLC cells to the treatment of Vismodegib with increased reactive oxygen species (ROS) and activated Caspase 3. Furthermore, combination use of Vismodegib and CQ in vivo also resulted in the generation of ROS and activation of Caspase 3 in xenograft NSCLC tissues, which finally caused the necrosis in the tumors. Our results demonstrated that autophagy protected the NSCLCs from Vismodegib by restricting the production of ROS and highlighted an approach for future treatment of NSCLC by combination use of Vismodegib and autophagy inhibitors.