PMID- 21215704 OWN - NLM STAT- MEDLINE DCOM- 20110314 LR - 20220408 IS - 1878-3686 (Electronic) IS - 1535-6108 (Print) IS - 1535-6108 (Linking) VI - 19 IP - 1 DP - 2011 Jan 18 TI - AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. PG - 58-71 LID - 10.1016/j.ccr.2010.10.031 [doi] AB - Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone. CI - Copyright A(c) 2011 Elsevier Inc. All rights reserved. FAU - Chandarlapaty, Sarat AU - Chandarlapaty S AD - Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. FAU - Sawai, Ayana AU - Sawai A FAU - Scaltriti, Maurizio AU - Scaltriti M FAU - Rodrik-Outmezguine, Vanessa AU - Rodrik-Outmezguine V FAU - Grbovic-Huezo, Olivera AU - Grbovic-Huezo O FAU - Serra, Violeta AU - Serra V FAU - Majumder, Pradip K AU - Majumder PK FAU - Baselga, Jose AU - Baselga J FAU - Rosen, Neal AU - Rosen N LA - eng GR - K08-CA134833/CA/NCI NIH HHS/United States GR - 250244/ERC_/European Research Council/International GR - K08 CA134833-03/CA/NCI NIH HHS/United States GR - P01 CA094060/CA/NCI NIH HHS/United States GR - K08 CA134833/CA/NCI NIH HHS/United States GR - K08 CA134833-01A1/CA/NCI NIH HHS/United States GR - K08 CA134833-02/CA/NCI NIH HHS/United States GR - P01-CA094060/CA/NCI NIH HHS/United States GR - L30 CA123387/CA/NCI NIH HHS/United States GR - P01 CA094060-08/CA/NCI NIH HHS/United States GR - L30 CA123387-02A2/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110106 PL - United States TA - Cancer Cell JT - Cancer cell JID - 101130617 RN - 0 (Akt-I-1,2 compound) RN - 0 (Benzylamines) RN - 0 (Forkhead Transcription Factors) RN - 0 (Multiprotein Complexes) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Proteins) RN - 0 (Quinazolines) RN - 0 (Quinoxalines) RN - 0 (RNA, Small Interfering) RN - 0VUA21238F (Lapatinib) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - S65743JHBS (Gefitinib) SB - IM MH - Animals MH - Benzylamines/pharmacology/therapeutic use MH - Breast Neoplasms/drug therapy/metabolism/pathology MH - Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/pathology MH - Cell Line, Tumor MH - Drug Therapy, Combination MH - Feedback, Physiological/drug effects/*physiology MH - Female MH - Forkhead Transcription Factors/antagonists & inhibitors/genetics/metabolism MH - Gefitinib MH - Gene Expression/drug effects MH - Gene Expression Regulation, Neoplastic/drug effects/*physiology MH - Humans MH - Lapatinib MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice MH - Mice, Nude MH - Models, Biological MH - Multiprotein Complexes MH - Neoplasms/metabolism MH - Phosphorylation/drug effects MH - Promoter Regions, Genetic/genetics MH - Protein Binding/drug effects/genetics MH - Protein Kinase Inhibitors/pharmacology/therapeutic use MH - Proteins/antagonists & inhibitors MH - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/genetics/*metabolism MH - Quinazolines/pharmacology/therapeutic use MH - Quinoxalines/pharmacology/therapeutic use MH - RNA, Small Interfering/genetics MH - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/*metabolism MH - Receptor, ErbB-2/antagonists & inhibitors/metabolism MH - Receptor, ErbB-3/genetics/metabolism MH - Receptor, IGF Type 1/genetics/metabolism MH - Receptor, Insulin/genetics/metabolism MH - Signal Transduction/drug effects/*physiology MH - TOR Serine-Threonine Kinases MH - Up-Regulation/genetics MH - Xenograft Model Antitumor Assays PMC - PMC3025058 MID - NIHMS250123 EDAT- 2011/01/11 06:00 MHDA- 2011/03/15 06:00 PMCR- 2012/01/18 CRDT- 2011/01/11 06:00 PHST- 2010/02/06 00:00 [received] PHST- 2010/07/16 00:00 [revised] PHST- 2010/10/14 00:00 [accepted] PHST- 2011/01/11 06:00 [entrez] PHST- 2011/01/11 06:00 [pubmed] PHST- 2011/03/15 06:00 [medline] PHST- 2012/01/18 00:00 [pmc-release] AID - S1535-6108(10)00433-2 [pii] AID - 10.1016/j.ccr.2010.10.031 [doi] PST - ppublish SO - Cancer Cell. 2011 Jan 18;19(1):58-71. doi: 10.1016/j.ccr.2010.10.031. Epub 2011 Jan 6.