mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling


High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.

DOI: 10.1007/s10495-014-1066-0

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@article{Zhang2014mTORAI, title={mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling}, author={Huiyuan Zhang and Jun Dou and Hanry Yu and Yanling Zhao and Yihui Fan and Jin Quan Cheng and Xin Xu and Wei Liu and Shan Guan and Zhenghu Chen and Yan Shi and Roma H. Patel and Sanjeev A. Vasudevan and Peter E. Zage and Hong Zhang and Jed G. Nuchtern and Eugene Kim and Songbin Fu and Jianhua Yang}, journal={Apoptosis}, year={2014}, volume={20}, pages={50-62} }