serval:BIB_71959E046B2F
Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity.
10.1155/2017/1726078
28280521
Faes
S.
author
Demartines
N.
author
Dormond
O.
author
article
review
2017
Oxidative medicine and cellular longevity
1942-0994
1942-0994
journal
2017
1726078
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.
Animals
Drug Resistance, Neoplasm/drug effects
Drug Resistance, Neoplasm/genetics
Humans
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Review
Publication Status: ppublish
University of Lausanne
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