Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling Academic Article uri icon


MeSH Major

  • MAP Kinase Signaling System
  • Neoplasms
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt


  • The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF-MEK-ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2(+) cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.

publication date

  • January 2014



  • Academic Article



  • eng

PubMed Central ID

  • PMC4049524

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-13-0611

PubMed ID

  • 24436048

Additional Document Info

start page

  • 334

end page

  • 47


  • 4


  • 3