title: Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling.
abstract: 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.
authors.affiliation: 1Program in Molecular Pharmacology; 2Human Oncology and Pathogenesis Program; 3Program in Cell Biology, Memorial Sloan-Kettering Cancer Center; 4Weill Cornell Medical College, New York, New York; and 5Bayer HealthCare, Global Drug Discovery, Berlin, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Will
authors.forename: Alice Can Ran
authors.initials: AC
authors.lastname: Qin
authors.forename: Weiyi
authors.initials: W
authors.lastname: Toy
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yao
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rodrik-Outmezguine
authors.forename: Claudia
authors.initials: C
authors.lastname: Schneider
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Huang
authors.forename: Prashant
authors.initials: P
authors.lastname: Monian
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Ningshu
authors.initials: N
authors.lastname: Liu
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D000077341:Lapatinib; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011799:Quinazolines; C548887:MK 2206; C000589253:copanlisib