title: AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity.
abstract: 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.
authors.affiliation: Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Ayana
authors.initials: A
authors.lastname: Sawai
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rodrik-Outmezguine
authors.forename: Olivera
authors.initials: O
authors.lastname: Grbovic-Huezo
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Majumder
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000077341:Lapatinib; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011506:Proteins / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001596:Benzylamines; D051858:Forkhead Transcription Factors; D000077156:Gefitinib; D000077341:Lapatinib; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D011810:Quinoxalines; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases; C501521:Akt-I-1,2 compound; C508053:ERBB2 protein, human