PMID- 28757207 OWN - NLM STAT- MEDLINE DCOM- 20170925 LR - 20211204 IS - 1097-4164 (Electronic) IS - 1097-2765 (Print) IS - 1097-2765 (Linking) VI - 67 IP - 3 DP - 2017 Aug 3 TI - Focal Adhesion- and IGF1R-Dependent Survival and Migratory Pathways Mediate Tumor Resistance to mTORC1/2 Inhibition. PG - 512-527.e4 LID - S1097-2765(17)30491-4 [pii] LID - 10.1016/j.molcel.2017.06.033 [doi] AB - Aberrant signaling by the mammalian target of rapamycin (mTOR) contributes to the devastating features of cancer cells. Thus, mTOR is a critical therapeutic target and catalytic inhibitors are being investigated as anti-cancer drugs. Although mTOR inhibitors initially block cell proliferation, cell viability and migration in some cancer cells are quickly restored. Despite sustained inhibition of mTORC1/2 signaling, Akt, a kinase regulating cell survival and migration, regains phosphorylation at its regulatory sites. Mechanistically, mTORC1/2 inhibition promotes reorganization of integrin/focal adhesion kinase-mediated adhesomes, induction of IGFR/IR-dependent PI3K activation, and Akt phosphorylation via an integrin/FAK/IGFR-dependent process. This resistance mechanism contributes to xenograft tumor cell growth, which is prevented with mTOR plus IGFR inhibitors, supporting this combination as a therapeutic approach for cancers. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Yoon, Sang-Oh AU - Yoon SO AD - Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: syoon1@uic.edu. FAU - Shin, Sejeong AU - Shin S AD - Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Karreth, Florian A AU - Karreth FA AD - Department of Medicine, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Buel, Gwen R AU - Buel GR AD - Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Jedrychowski, Mark P AU - Jedrychowski MP AD - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Plas, David R AU - Plas DR AD - Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267, USA. FAU - Dedhar, Shoukat AU - Dedhar S AD - Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada. FAU - Gygi, Steven P AU - Gygi SP AD - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Roux, Philippe P AU - Roux PP AD - Institute for Research in Immunology and Cancer (IRIC), Universite de Montreal, Montreal, QC H3T 1J4, Canada. FAU - Dephoure, Noah AU - Dephoure N AD - Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA. FAU - Blenis, John AU - Blenis J AD - Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: jblenis@med.cornell.edu. LA - eng GR - R01 CA133164/CA/NCI NIH HHS/United States GR - R01 HL121266/HL/NHLBI NIH HHS/United States GR - R01 CA046595/CA/NCI NIH HHS/United States GR - R37 CA046595/CA/NCI NIH HHS/United States GR - R01 CA168815/CA/NCI NIH HHS/United States GR - R01 GM051405/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20170727 PL - United States TA - Mol Cell JT - Molecular cell JID - 9802571 RN - 0 (IGF1R protein, human) RN - 0 (Integrin alpha2) RN - 0 (Multiprotein Complexes) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Receptors, Somatomedin) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.2 (Focal Adhesion Kinase 1) RN - EC 2.7.10.2 (PTK2 protein, human) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology MH - Breast Neoplasms/*drug therapy/enzymology/genetics/pathology MH - Cell Line, Tumor MH - Cell Movement/*drug effects MH - Cell Survival/drug effects MH - *Drug Resistance, Neoplasm MH - Female MH - Focal Adhesion Kinase 1/genetics/*metabolism MH - Humans MH - Integrin alpha2/metabolism MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Melanoma/*drug therapy/enzymology/pathology MH - Mice, Nude MH - Multiprotein Complexes/*antagonists & inhibitors/metabolism MH - Neoplasm Invasiveness MH - Phosphatidylinositol 3-Kinase/metabolism MH - Phosphorylation MH - Protein Kinase Inhibitors/*pharmacology MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - RNA Interference MH - Receptor, IGF Type 1 MH - Receptors, Somatomedin/*antagonists & inhibitors/genetics/metabolism MH - Signal Transduction/drug effects MH - Skin Neoplasms/*drug therapy/enzymology/genetics/pathology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Time Factors MH - Transfection MH - Tumor Burden/drug effects MH - Xenograft Model Antitumor Assays PMC - PMC5698809 MID - NIHMS890118 OTO - NOTNLM OT - Akt OT - dual mTORC1/2 inhibition OT - mTORC1 OT - mTORC2 OT - tumor resistance COIS- The authors declare no potential conflicts of interest. EDAT- 2017/08/02 06:00 MHDA- 2017/09/26 06:00 PMCR- 2018/08/03 CRDT- 2017/08/01 06:00 PHST- 2017/02/13 00:00 [received] PHST- 2017/05/24 00:00 [revised] PHST- 2017/06/27 00:00 [accepted] PHST- 2017/08/02 06:00 [pubmed] PHST- 2017/09/26 06:00 [medline] PHST- 2017/08/01 06:00 [entrez] PHST- 2018/08/03 00:00 [pmc-release] AID - S1097-2765(17)30491-4 [pii] AID - 10.1016/j.molcel.2017.06.033 [doi] PST - ppublish SO - Mol Cell. 2017 Aug 3;67(3):512-527.e4. doi: 10.1016/j.molcel.2017.06.033. Epub 2017 Jul 27.