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

Huiyuan Zhang, Jun Dou, Yang Yu, Yanling Zhao, Yihui Fan, Jin Cheng, Xin Xu, Wei Liu, Shan Guan, Zhenghu Chen, Yan Shi, Roma Patel, Sanjeev A. Vasudevan, Peter Zage, Hong Zhang, Jed G. Nuchtern, Eugene S. Kim, Songbin Fu, Jianhua Yang

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)50-62
Number of pages13
JournalApoptosis
Volume20
Issue number1
DOIs
StatePublished - Jan 2015

Keywords

  • Chemotherapy
  • Drug resistance
  • INK128
  • Neuroblastoma
  • mTOR inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

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