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Phosphoproteomics of MAPK inhibition in BRAF-mutated cells and a role for the lethal synergism of dual BRAF and CK2 inhibition.
Mol Cancer Ther. 2014 Jul; 13(7):1894-906.MC

Abstract

Activating mutations in the MAPK pathway are prevalent drivers of several cancers. The chief consequence of these mutations is a hyperactive ERK1/2 MAPK able to promote cell proliferation, producing a critical hallmark of metastatic disease. The biochemistry of the ERK pathway is well characterized; however, how the pathway achieves different outcomes in the face of genetic aberrations of cancer and subsequent treatment with chemical inhibitors is not clear. To investigate this, we used mass spectrometry to complete a global phosphoproteomic analysis of a BRAFV600E thyroid cancer cell line (SW1736) after treatment with the mutation-selective inhibitor vemurafenib (PLX4032) and MEK1/2 inhibitor selumetinib (AZD6244). We identified thousands of phosphorylation events orchestrated in BRAFV600E cells and performed kinase landscape analysis to identify putative kinases regulated in response to MAPK blockade. The abundance of phosphopeptides containing consensus motifs for acidophilic kinases increased after short-term inhibition with these compounds. We showed that coinhibition of the pleiotropic acidophilic protein kinase CK2 (CK2) and BRAFV600E synergistically reduced proliferation in patient-derived melanomas and thyroid cancer cells harboring the BRAF lesion. We investigated this mechanism and show a role for CK2 in controlling AKT activation that was not reliant on changes to PTEN or PDK1 phosphorylation. These findings highlight a role for CK2 blockade in potentiating the antiproliferative effects of BRAF and MEK inhibition in BRAF cancers.

Authors+Show Affiliations

Authors' Affiliations: Australian Proteome Analysis Facility, Department of Chemistry and Biomolecular Sciences, Macquarie University; and.Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.Authors' Affiliations: Australian Proteome Analysis Facility, Department of Chemistry and Biomolecular Sciences, Macquarie University; and mmolloy@proteome.org.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24825855

Citation

Parker, Robert, et al. "Phosphoproteomics of MAPK Inhibition in BRAF-mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition." Molecular Cancer Therapeutics, vol. 13, no. 7, 2014, pp. 1894-906.
Parker R, Clifton-Bligh R, Molloy MP. Phosphoproteomics of MAPK inhibition in BRAF-mutated cells and a role for the lethal synergism of dual BRAF and CK2 inhibition. Mol Cancer Ther. 2014;13(7):1894-906.
Parker, R., Clifton-Bligh, R., & Molloy, M. P. (2014). Phosphoproteomics of MAPK inhibition in BRAF-mutated cells and a role for the lethal synergism of dual BRAF and CK2 inhibition. Molecular Cancer Therapeutics, 13(7), 1894-906. https://doi.org/10.1158/1535-7163.MCT-13-0938
Parker R, Clifton-Bligh R, Molloy MP. Phosphoproteomics of MAPK Inhibition in BRAF-mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition. Mol Cancer Ther. 2014;13(7):1894-906. PubMed PMID: 24825855.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphoproteomics of MAPK inhibition in BRAF-mutated cells and a role for the lethal synergism of dual BRAF and CK2 inhibition. AU - Parker,Robert, AU - Clifton-Bligh,Roderick, AU - Molloy,Mark P, Y1 - 2014/05/13/ PY - 2014/5/15/entrez PY - 2014/5/16/pubmed PY - 2015/4/22/medline SP - 1894 EP - 906 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 13 IS - 7 N2 - Activating mutations in the MAPK pathway are prevalent drivers of several cancers. The chief consequence of these mutations is a hyperactive ERK1/2 MAPK able to promote cell proliferation, producing a critical hallmark of metastatic disease. The biochemistry of the ERK pathway is well characterized; however, how the pathway achieves different outcomes in the face of genetic aberrations of cancer and subsequent treatment with chemical inhibitors is not clear. To investigate this, we used mass spectrometry to complete a global phosphoproteomic analysis of a BRAFV600E thyroid cancer cell line (SW1736) after treatment with the mutation-selective inhibitor vemurafenib (PLX4032) and MEK1/2 inhibitor selumetinib (AZD6244). We identified thousands of phosphorylation events orchestrated in BRAFV600E cells and performed kinase landscape analysis to identify putative kinases regulated in response to MAPK blockade. The abundance of phosphopeptides containing consensus motifs for acidophilic kinases increased after short-term inhibition with these compounds. We showed that coinhibition of the pleiotropic acidophilic protein kinase CK2 (CK2) and BRAFV600E synergistically reduced proliferation in patient-derived melanomas and thyroid cancer cells harboring the BRAF lesion. We investigated this mechanism and show a role for CK2 in controlling AKT activation that was not reliant on changes to PTEN or PDK1 phosphorylation. These findings highlight a role for CK2 blockade in potentiating the antiproliferative effects of BRAF and MEK inhibition in BRAF cancers. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/24825855/Phosphoproteomics_of_MAPK_inhibition_in_BRAF_mutated_cells_and_a_role_for_the_lethal_synergism_of_dual_BRAF_and_CK2_inhibition_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24825855 DB - PRIME DP - Unbound Medicine ER -