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Supplementary Figure S2 from ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP
figureposted on 2023-03-31, 00:25 authored by Taru Muranen, Laura M. Selfors, Julie Hwang, Lisa L. Gallegos, Jonathan L. Coloff, Carson C. Thoreen, Seong A. Kang, David M. Sabatini, Gordon B. Mills, Joan S. Brugge
MYC and YAP expression mediate drug resistance towards PI3K/mTOR inhibition.
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ARTICLE ABSTRACTAberrant 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. Cancer Res; 76(24); 7168–80. ©2016 AACR.
Cell CycleSignal transduction pathwaysCell SignalingDrug ResistanceNovel mechanismsReversal of drug resistanceDrug TargetsOncoprotein & tumor suppressor drug targetsProgression, Invasion & MetastasisCell adhesion and extracellular matrixSmall Molecule AgentsTumor MicroenvironmentTumor-stromal cell interactions