ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP
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nihms826992.pdf
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Author(s)
Muranen, Taru
Selfors, Laura M.
Hwang, Julie
Gallegos, Lisa L.
Coloff, Jonathan L.
Mills, Gordon B.
Brugge, Joan S.
Thoreen, Carson C
Kang, Seong-Cheol
Sabatini, David
Date Issued
October 2016
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Citation
Muranen, Taru et al. “ERK and P38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP.” Cancer Research 76, 24 (October 2016): 7168–7180 © 2016 American Association for Cancer Research (AACR)
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1158/0008-5472.CAN-16-0155
