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Supplementary Figure S7 from Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS–ERK Signaling

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posted on 2023-04-03, 20:45 authored by Marie Will, Alice Can Ran Qin, Weiyi Toy, Zhan Yao, Vanessa Rodrik-Outmezguine, Claudia Schneider, Xiaodong Huang, Prashant Monian, Xuejun Jiang, Elisa de Stanchina, José Baselga, Ningshu Liu, Sarat Chandarlapaty, Neal Rosen

PDF file 1129K, Supplementary Figure S7. Combined MEK and AKT inhibition improves antitumor efficacy in vivo. Pulsatile administration of the PI3K inhibitor is effective. Related to main Figure 7

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ARTICLE 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. Cancer Discov; 4(3); 334–47. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 259

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