Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

Nature. 2016 Jun 9;534(7606):272-6. doi: 10.1038/nature17963. Epub 2016 May 18.


Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in 'N-of-1' cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we sought to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumours with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Cell Line, Tumor
  • Drug Resistance / drug effects*
  • Drug Resistance / genetics*
  • Female
  • Humans
  • Mice
  • Mutation / drug effects
  • Mutation / genetics*
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / classification
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary / genetics
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / chemistry
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays


  • Protein Kinase Inhibitors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases