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. Cancer Res; 76(24); 7168-80. ©2016 AACR.
authors.affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
authors.forename: Taru
authors.initials: T
authors.lastname: Muranen
authors.affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Selfors
authors.affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
authors.forename: Julie
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Gallegos
authors.affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Coloff
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts.|Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Carson C
authors.initials: CC
authors.lastname: Thoreen
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts.|Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Seong A
authors.initials: SA
authors.lastname: Kang
authors.affiliation: Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts.|Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts. joan_brugge@hms.harvard.edu.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D018613:Microscopy, Confocal; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000715470:MAS1 protein, human; C489427:MYC protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases