@article{c72920d248e34a87849eb318187eb738,
title = "ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP",
abstract = "Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell-targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors.",
author = "Taru Muranen and Selfors, {Laura M.} and Julie Hwang and Gallegos, {Lisa L.} and Coloff, {Jonathan L.} and Thoreen, {Carson C.} and Kang, {Seong A.} and Sabatini, {David M.} and Mills, {Gordon B.} and Brugge, {Joan S.}",
note = "Funding Information: We thank Dennis Slamon for providing cell lines, Jennifer Waters and Nikon Imaging Center at Harvard Medical School for assistance with microscopy, Deepak Sampath (Genentech) for providing GNE493, Julio Aguirre-Ghiso for providing p38a construct, Angie Martinez-Gakidis for critical reading of the manuscript, Valerie Pireaux for technical help, Shomit Sengupta and members of the Brugge laboratory for helpful discussions. This work was supported by grant NIC-5K99CA180221 and Laura Ziskin Memorial Award (Entertainment Industry Foundation to T. Muranen). J.S. Brugge received a gift from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. D.M. Sabatini was supported by NIH grants R01 CA103866 and AI47389. G.B. Mills has been supported by grants 0099031 U54CA112970, BCRF 01-06-00332, Komen Foundation (KG08169404 and SAC110052), MDACC CCSG grant P30 CA016672, and a gift from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2016 AACR.",
year = "2016",
month = dec,
day = "15",
doi = "10.1158/0008-5472.CAN-16-0155",
language = "English (US)",
volume = "76",
pages = "7168--7180",
journal = "Cancer Research",
issn = "0008-5472",
number = "24",
}