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      The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)

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          Abstract

          Protein phosphorylation is an important cellular regulatory mechanism as many enzymes and receptors are activated/deactivated by phosphorylation and dephosphorylation events, by means of kinases and phosphatases. In particular, the protein kinases are responsible for cellular transduction signaling and their hyperactivity, malfunction or overexpression can be found in several diseases, mostly tumors. Therefore, it is evident that the use of kinase inhibitors can be valuable for the treatment of cancer. In this review, we discuss the mechanism of action of phosphorylation, with particular attention to the importance of phosphorylation under physiological and pathological conditions. We also discuss the possibility of using kinase inhibitors in the treatment of tumors.

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          Cancer genes and the pathways they control.

          Bert Vogelstein, Kenneth W. Kinzler (2004)
          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
          Article 0 comments Cited 952 times – based on 0 reviews     Review now
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            Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

            James Larkin, Paolo Ascierto, Brigitte Dréno … (2014)
            The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).
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              Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

              Klarisa Rikova, Ailan Guo, Qingfu Zeng … (2008)
              Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
              Article 0 comments Cited 637 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Med
                Journal ID (iso-abbrev): Int. J. Mol. Med
                Journal ID (publisher-id): IJMM
                Title: International Journal of Molecular Medicine
                Publisher: D.A. Spandidos
                ISSN (Print): 1107-3756
                ISSN (Electronic): 1791-244X
                Publication date (Print): August 2017
                Publication date (Electronic): 22 June 2017
                Publication date PMC-release: 22 June 2017
                Volume: 40
                Issue: 2
                Pages: 271-280
                Affiliations
                Department of Clinical and Experimental Medicine, Foggia University, I-71122 Foggia, Italy
                Author notes
                Correspondence to: Professor Lorenzo Lo Muzio, Department of Clinical and Experimental Medicine, Foggia University, Via Rovelli 48, I-71122 Foggia, Italy, E-mail: lorenzo.lomuzio@ 123456unifg.it
                Article
                Publisher ID: ijmm-40-02-0271
                DOI: 10.3892/ijmm.2017.3036
                PMC ID: 5500920
                PubMed ID: 28656226
                SO-VID: 99ccf8fe-3bbf-4f4f-bf6e-9c36467ae84d
                Copyright © Copyright: © Ardito et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 17 January 2017
                Date accepted : 11 May 2017
                Categories
                Subject: Articles

                Keywords: protein phosphorylation,kinase,phosphatase,phospho-signaling networks,cancer,drug target
                Data availability:
                Keywords: protein phosphorylation, kinase, phosphatase, phospho-signaling networks, cancer, drug target

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