ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP
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 o...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
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American Association for Cancer Research (AACR)
2018
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| Online Access: | http://hdl.handle.net/1721.1/116784 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826200515562700800 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 |
| author_sort | Muranen, Taru |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:37:40Z |
| format | Article |
| id | mit-1721.1/116784 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:37:40Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1167842022-09-27T20:51:51Z 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. Mills, Gordon B. Brugge, Joan S. Thoreen, Carson C Kang, Seong-Cheol Sabatini, David Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Thoreen, Carson C Kang, Seong-Cheol Sabatini, David 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. National Institutes of Health (U.S.) (Grant R01CA103866) National Institutes of Health (U.S.) (Grant AI47389) 2018-07-05T13:44:25Z 2018-07-05T13:44:25Z 2016-10 2016-09 2018-07-03T18:28:32Z Article http://purl.org/eprint/type/JournalArticle 0008-5472 1538-7445 http://hdl.handle.net/1721.1/116784 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) https://orcid.org/0000-0002-1446-7256 http://dx.doi.org/10.1158/0008-5472.CAN-16-0155 Cancer Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | 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 ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP |
| title | ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP |
| title_full | ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP |
| title_fullStr | ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP |
| title_full_unstemmed | ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP |
| title_short | ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP |
| title_sort | erk and p38 mapk activities determine sensitivity to pi3k mtor inhibition via regulation of myc and yap |
| url | http://hdl.handle.net/1721.1/116784 https://orcid.org/0000-0002-1446-7256 |
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