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

   

Authors:	Will, M.; Qin, A. C. R.; Toy, W.; Yao, Z.; Rodrik-Outmezguine, V. ; Schneider, C.; Huang, X.; Monian, P.; Jiang, X.; de Stanchina, E.; Baselga, J.; Liu, N.; Chandarlapaty, S.; Rosen, N.
Article 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. SIGNIFICANCE: We show that the RAS-ERK pathway is a key downstream effector pathway of oncogenic PI3K. Coordinate downregulation of AKT and ERK is necessary for induction of apoptosis and antitumor activity and can be accomplished with pulsatile dosing, which will likely decrease toxicity and allow administration of therapeutic doses. ©2014 AACR.
Keywords:	signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; protein expression; protein phosphorylation; unclassified drug; nonhuman; animal cell; mouse; cell death; apoptosis; breast cancer; lung non small cell cancer; epidermal growth factor receptor 2; caspase 3; antineoplastic activity; tumor regression; phosphatidylinositol 3 kinase; mammalian target of rapamycin; immunoblotting; ras protein; large cell lymphoma; doxycycline; guanosine triphosphate; fluorescence activated cell sorting; lapatinib; cyclin d; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; phosphatidylinositol 3 kinase inhibitor; caspase 7; azd 8055; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; article; copanlisib; phosphatidylinositol 3, 4, 5 trisphosphate 3 phosphatase
Journal Title:	Cancer Discovery
Volume:	4
Issue:	3
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2014-03-01
Start Page:	334
End Page:	348
Language:	English
DOI:	10.1158/2159-8290.cd-13-0611
PROVIDER:	scopus
PUBMED:	24436048
PMCID:	PMC4049524
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84894557306&partnerID=40&md5=8fc805b8a93fd98cbd71e388f1ff73a3
Notes:	Cited By (since 1996):1 -- Export Date: 2 April 2014 -- Source: Scopus