title: Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity.
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.
authors.affiliation: Department of Visceral Surgery, Lausanne University Hospital, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland.
authors.forename: Seraina
authors.initials: S
authors.lastname: Faes
authors.affiliation: Department of Visceral Surgery, Lausanne University Hospital, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.affiliation: Department of Visceral Surgery, Lausanne University Hospital, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland.
authors.forename: Olivier
authors.identifier: 0000-0002-6418-1782
authors.initials: O
authors.lastname: Dormond
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases