NOTCH and PI3K-AKT pathways intertwined

Cancer Cell. 2007 Nov;12(5):411-3. doi: 10.1016/j.ccr.2007.10.027.


Constitutive signaling by the NOTCH1 receptor contributes to more than half of all cases of T cell acute lymphoblastic leukemia (T-ALL). However, blocking the proteolytic activation of NOTCH1 with gamma-secretase inhibitors (GSIs) fails to alter the growth of some T-ALL cell lines carrying the mutated receptor. A recent report by Palomero et al. in Nature Medicine identifies loss of PTEN as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of "oncogene addiction" from the NOTCH1 to the PI3K/AKT pathway. This novel observation suggests the need to simultaneously inhibit both pathways as a means to improve therapeutic efficacy in human T-ALL.

MeSH terms

  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Leukemia, T-Cell / metabolism
  • Models, Biological
  • Mutation
  • Oncogenes / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, Notch1 / metabolism*
  • Signal Transduction
  • Transcription, Genetic


  • NOTCH1 protein, human
  • Receptor, Notch1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt