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Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer.
Clin Cancer Res. 2014 May 15; 20(10):2516-22.CC

Abstract

The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF and MAP-ERK kinase (MEK) inhibitor (trametinib) is significantly more active in patients with BRAF-mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of extracellular signal-regulated kinase (ERK). Such adaptive changes in tumor cell signaling networks allow bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR, and many receptor tyrosine kinases such as EGF receptor (EGFR) and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single-agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single-agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses.

Authors+Show Affiliations

Authors' Affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina glj@med.unc.edu.Authors' Affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.Authors' Affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.Authors' Affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.Authors' Affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24664307

Citation

Johnson, Gary L., et al. "Molecular Pathways: Adaptive Kinome Reprogramming in Response to Targeted Inhibition of the BRAF-MEK-ERK Pathway in Cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 20, no. 10, 2014, pp. 2516-22.
Johnson GL, Stuhlmiller TJ, Angus SP, et al. Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer. Clin Cancer Res. 2014;20(10):2516-22.
Johnson, G. L., Stuhlmiller, T. J., Angus, S. P., Zawistowski, J. S., & Graves, L. M. (2014). Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 20(10), 2516-22. https://doi.org/10.1158/1078-0432.CCR-13-1081
Johnson GL, et al. Molecular Pathways: Adaptive Kinome Reprogramming in Response to Targeted Inhibition of the BRAF-MEK-ERK Pathway in Cancer. Clin Cancer Res. 2014 May 15;20(10):2516-22. PubMed PMID: 24664307.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer. AU - Johnson,Gary L, AU - Stuhlmiller,Timothy J, AU - Angus,Steven P, AU - Zawistowski,Jon S, AU - Graves,Lee M, Y1 - 2014/03/24/ PY - 2014/3/26/entrez PY - 2014/3/26/pubmed PY - 2015/2/11/medline SP - 2516 EP - 22 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 20 IS - 10 N2 - The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF and MAP-ERK kinase (MEK) inhibitor (trametinib) is significantly more active in patients with BRAF-mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of extracellular signal-regulated kinase (ERK). Such adaptive changes in tumor cell signaling networks allow bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR, and many receptor tyrosine kinases such as EGF receptor (EGFR) and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single-agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single-agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/24664307/Molecular_pathways:_adaptive_kinome_reprogramming_in_response_to_targeted_inhibition_of_the_BRAF_MEK_ERK_pathway_in_cancer_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24664307 DB - PRIME DP - Unbound Medicine ER -