AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity

Cancer Cell. 2011 Jan 18;19(1):58-71. doi: 10.1016/j.ccr.2010.10.031. Epub 2011 Jan 6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzylamines / pharmacology
  • Benzylamines / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Drug Therapy, Combination
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology*
  • Female
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gefitinib
  • Gene Expression / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Lapatinib
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Models, Biological
  • Multiprotein Complexes
  • Neoplasms / metabolism
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • Quinoxalines / pharmacology
  • Quinoxalines / therapeutic use
  • RNA, Small Interfering / genetics
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-3 / genetics
  • Receptor, ErbB-3 / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases
  • Up-Regulation / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Akt-I-1,2 compound
  • Benzylamines
  • Forkhead Transcription Factors
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Proteins
  • Quinazolines
  • Quinoxalines
  • RNA, Small Interfering
  • Lapatinib
  • TOR Serine-Threonine Kinases
  • ERBB2 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Gefitinib