ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP

Taru Muranen, Laura M. Selfors, Julie Hwang, Lisa L. Gallegos, Jonathan L. Coloff, Carson C. Thoreen, Seong A. Kang, David M. Sabatini, Gordon Mills, Joan S. Brugge

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)7168-7180
Number of pages13
JournalCancer Research
Volume76
Issue number24
DOIs
StatePublished - Dec 15 2016
Externally publishedYes

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p38 Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Tumor Escape
Neoplasms
Proto-Oncogenes
Cell- and Tissue-Based Therapy
Phosphotransferases
Up-Regulation
Animal Models
Therapeutics
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Muranen, T., Selfors, L. M., Hwang, J., Gallegos, L. L., Coloff, J. L., Thoreen, C. C., ... Brugge, J. S. (2016). ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP. Cancer Research, 76(24), 7168-7180. https://doi.org/10.1158/0008-5472.CAN-16-0155

ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP. / Muranen, Taru; Selfors, Laura M.; Hwang, Julie; Gallegos, Lisa L.; Coloff, Jonathan L.; Thoreen, Carson C.; Kang, Seong A.; Sabatini, David M.; Mills, Gordon; Brugge, Joan S.

In: Cancer Research, Vol. 76, No. 24, 15.12.2016, p. 7168-7180.

Research output: Contribution to journalArticle

Muranen, T, Selfors, LM, Hwang, J, Gallegos, LL, Coloff, JL, Thoreen, CC, Kang, SA, Sabatini, DM, Mills, G & Brugge, JS 2016, 'ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP', Cancer Research, vol. 76, no. 24, pp. 7168-7180. https://doi.org/10.1158/0008-5472.CAN-16-0155
Muranen, Taru ; Selfors, Laura M. ; Hwang, Julie ; Gallegos, Lisa L. ; Coloff, Jonathan L. ; Thoreen, Carson C. ; Kang, Seong A. ; Sabatini, David M. ; Mills, Gordon ; Brugge, Joan S. / ERK and p38 MAPK activities determine sensitivity to PI3K/mTOR inhibition via regulation of MYC and YAP. In: Cancer Research. 2016 ; Vol. 76, No. 24. pp. 7168-7180.
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