The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
MEK Inhibition Leads to PI3K/AKT Activation by Relieving a Negative Feedback on ERBB Receptors
Open accessPublished version of a preprint
Abstract
The phosphoinositide 3-kinase (PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-agent targeted therapies. In this study, we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers. We found that MEK inhibitor–induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2. Mutation of this amino acid led to increased ERBB receptor activation and upregulation of the ERBB3/PI3K/AKT signaling pathway, which was no longer responsive to MEK inhibition. Taken together, these results elucidate an important, dominant feedback network regulating central oncogenic pathways in human cancer. Cancer Res; 72(13); 3228–37. ©2012 AACR.
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“Inhibition of either PI3K/mTOR or ERK signaling often relieves feedback inhibition of the other and causes its activation46,47.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [47]
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“In NSCLCs and CRCs, KRASG12C inhibition leads to an accumulation of activated upstream EGFR and/or other ERBB family members, which facilitates escape from KRASG12C-inhibitor monotherapy110,121–124.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [123]
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Cites
Defining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833
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Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R., et al. (2011) · Science · doi:10.1126/science.1196371 · Cited by 2,600
Self-citationmTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
O'Reilly, K. E., Rojo, F., She, Q.-B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2925 · Cited by 2,561
Targeting PI3K signalling in cancer: opportunities, challenges and limitations
Engelman, J. A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2664 · Cited by 2,445
Self-citationPreexistence and clonal selection of MET amplification in EGFR mutant NSCLC
Turke, A. B., Zejnullahu, K., Wu, Y.-L., Song, Y., Dias-Santagata, D., Lifshits, E., Toschi, L., Rogers, A., Mok, T., Sequist, L., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.11.022 · Cited by 1,059
Self-citationAKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., Majumder, P. K., Baselga, J., & Rosen, N. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.10.031 · Cited by 967
Sun, S., Rosenberg, L. M., Wang, X., Zhou, Z., Yue, P., Fu, H., & Khuri, F. R. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0917 · Cited by 800
Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment
Jura, N., Endres, N., Engel, K., Deindl, S., Das, R., Lamers, M. H., Wemmer, D. E., Zhang, X., & Kuriyan, J. (2009) · Cell · doi:10.1016/j.cell.2009.04.025 · Cited by 609
Yeh, T. C., Marsh, V., Bernat, B. A., Ballard, J., Colwell, H., Evans, R. J., Parry, J., Smith, D. J., Brandhuber, B. J., Gross, S. D., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1150 · Cited by 578
Serra, V., Scaltriti, M., Prudkin, L., Eichhorn, P. J. A., Ibrahim, Y. H., Chandarlapaty, S., Markman, B., Rodríguez, O., Guzmán, M., Rodriguez, S., et al. (2011) · Oncogene · doi:10.1038/onc.2010.626 · Cited by 541
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Self-citationA Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer
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Metadata
- Authors
- Turke, A. B., Song, Y., Costa, C., Cook, R., Arteaga, C. L., Asara, J. M., & Engelman, J. A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Engelman, Jeffrey A.
- ORCID
- Venue
- Cancer Research
- Published
- 2012-07-01
- Volume
- 72
- Issue
- 13
- Pages
- 3228-3237
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3515079
- OpenAlex
- W2105437003
- Cited by
- 368
- References
- 37
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 22 · 2023: 30 · 2022: 32 · 2021: 21 · 2020: 27 · 2019: 25 · 2018: 27 · 2017: 30 · 2016: 36 · 2015: 25 · 2014: 30 · 2013: 18 · 2012: 3
- FWCI
- 9.76
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50 CA98131, R01 CA80195, P50CA127003, R01CA166480, U01CA141457, R01CA080195, R01CA140594, P50CA090578, K08CA120060, P50CA098131, P01CA120964, R01CA137008, P30CA006516)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- MEK inhibition, PI3K/Akt signaling, HER3, ErbB receptors, EGFR, HER2, negative feedback loop, Raf/MEK/ERK pathway, drug resistance, cancer pathways
- MeSH terms
- Cell Line, Enzyme Activation, Feedback, Flow Cytometry, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, Receptor Protein-Tyrosine Kinases, Mitogen-Activated Protein Kinase Kinases, Proto-Oncogene Proteins c-akt, Tandem Mass Spectrometry, Gene Knockdown Techniques
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