Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity

Oxid Med Cell Longev. 2017;2017:1726078. doi: 10.1155/2017/1726078. Epub 2017 Feb 9.

Abstract

Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors. Intriguingly, the heterogeneity of mTORC1 activity also occurs towards its substrates at the single cell level, as mutually exclusive pattern of activation of mTORC1 downstream effectors has been reported in tumors. After briefly describing mTORC1 biology and the use of mTORC1 inhibitors in patients, this review will give an overview on concepts of resistance to mTORC1 inhibition in cancer with a particular focus on intratumoral heterogeneity of mTORC1 activity.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / genetics*
  • Mutation / genetics*
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics*

Substances

  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1