Supplementary Figure S2 from ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP

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posted 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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Entertainment Industry Foundation

NIH

BCRF

Komen Foundation

MDACC CCSG

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ARTICLE 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. Cancer Res; 76(24); 7168–80. ©2016 AACR.

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Keywords

Cell Cycle Signal transduction pathways Cell Signaling Drug Resistance Novel mechanisms Reversal of drug resistance Drug Targets Oncoprotein & tumor suppressor drug targets Progression, Invasion & Metastasis Cell adhesion and extracellular matrix Small Molecule Agents Tumor Microenvironment Tumor-stromal cell interactions

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