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Cancers 2018, 10(3), 63; https://doi.org/10.3390/cancers10030063
Kinases and Cancer
Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria
Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Sauletekio al. 7, LT-10257 Vilnius, Lithuania
MAP Kinase Resource, Bioinformatics, Melchiorstrasse 9, 3027 Bern, Switzerland
CALIPHO Group, SIB Swiss Institute of Bioinformatics, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland
Faculty of Medicine; University of Geneva; 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland
Authors to whom correspondence should be addressed.
Received: 27 February 2018 / Accepted: 28 February 2018 / Published: 1 March 2018
Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases. Phosphorylation is one of the critical mechanisms for regulating different cellular functions, such as proliferation, cell cycle, apoptosis, motility, growth, differentiation, among others. Deregulation of kinase activity can result in dramatic changes in these processes. Moreover, deregulated kinases are frequently found to be oncogenic and can be central for the survival and spread of cancer cells . There are several ways for kinases to become involved in cancers: mis-regulated expression and/or amplification, aberrant phosphorylation, mutation, chromosomal translocation, and epigenetic regulation.
The CALIPHO group of the SIB Swiss Institute of Bioinformatics develops neXtProt, a knowledge base focused on human proteins . CALIPHO has fully annotated 300 of the best characterized protein kinases with respect to their normal function and their role in disease and pathogenesis. It has generated a corpus of around 30,000 statements about each of these proteins. This data is being progressively integrated into the neXtProt database. As of February 2018, neXtProt has integrated the GO biological processes annotations captured in the framework of this project, representing both the signaling pathways in which each kinase is implicated, as well as the role of those pathways in higher level processes, such as apoptosis, cellular proliferation, and development. These functions may give insights into the mechanisms of pathogenesis of each different kinase. This first set of annotation comprises approximately 5000 different statements, extracted from over 5000 publications. In the neXtProt web interface, this data can be identified by the ‘Source’ set as neXtProt in the right-hand side of the annotation table visible on the neXtProt page for each entry (https://www.nextprot.org/) (see Figure 1).
Two datasets remain to be integrated: the first contains approximately 11,000 annotations describing the substrates and phosphorylation sites of these substrates, which can provide valuable insight to identify potential drug targets, or, importantly, predict undesirable side effects.
The second dataset contains close to 6000 manually extracted annotations of great interest for cancer researchers: the potential use of each kinase as biomarkers (prognostic, diagnostic, or predictive); any reported misregulation of expression in disease, at the mRNA and/or protein, or resulting from aberrant epigenetic regulation; genetic variants associated with diseases, and finally, the use of the protein kinase as a disease model.
Kinase amplifications could be used as diagnostic, prognostic, and predictive biomarkers in various cancer types. The best examples of kinase gene amplifications could be EGFR in non-small cell lung , colorectal , bladder  pancreatic , and breast  cancers; ERBB2 in breast , esophageal , gastric , and ovarian cancers ; MET in on-small cell lung , gastric , and colorectal cancers ; and AKT2 in pancreatic  and ovarian cancers . Similarly, overexpression of mRNA or protein kinases are very well known in cancers and used as biomarker. Again, EGFR , ERBB2 , EPHA2 , and AKT2  could be a good example.
The phosphorylation of some kinases, such as EGFR [21,22], ERBB2 [21,23,24], ERK , AURKA , p38 , and AKT [28,29] is associated with prognosis in cancers and, in some cases, is a better marker than expression of the kinase. In addition, the substrates of kinases are known to be biomarkers in various cancers. For example SCH1 , p21Cip1 , p27Kip1 , androgen receptor , and retinoblastoma protein (RB)  have been shown to be prognostic biomarkers in breast and pancreatic cancer.
One of the most extreme paths to the cancer development and progression is the mutations of the various genes, including kinases. The mutated kinases can become constitutively active and thus cause diverse cellular anomalies, leading to cancer initiation or growth. Probably the most well-known mutated kinase is BRAF, which is frequently mutated on Val-600 (p.V600E) [35,36] and is a driver mutation in several cancers, including colorectal cancer , melanoma , thyroid cancer  and non-small cell lung cancer . Other frequent mutations occur in KIT , EGFR , and FTL3 .
Chromosomal translocations can also be cancer drivers. The most well-known translocation creates what is known as the Philadelphia chromosome, it is a translocation that creates a fusion of BCR with the ABL1 tyrosine kinase fusion with BCR and the subsequent constitutive activation of the kinase. Around 95% of patients with chronic myelogenous leukemia have this abnormality , as well as 25% with acute lymphoblastic leukemia . Another famous translocation is EML4-ALK, first detected in lung adenocarcinomas and later found in different types of lung cancers . FIP1L1-PDGFRA is another example of kinase translocation, resulting in eosinophilias and leukemias .
One of the fields for a better understanding of cancer biology is epigenetics, which includes modifications in chromatin structure through DNA chemical alteration, post-translational modifications of DNA bound proteins as well as gene expression regulation through non-coding RNAs, the processes all of which are involved in tumorigenesis and metastatic predisposition. Some kinases have been shown to be regulated by epigenetic mechanisms, such as RET [46,47], AATK , EPHA5 , CHK2 , and PKD1 .
Because of the pivotal function of kinases in cell biology and their role in numerous cancers, an intensive search for kinase inhibitors both for research purposes and for therapeutic usage has been ongoing for several decades. The first inhibitor, which provided the proof of principle that abnormal kinase inhibition can be used for cancer therapy, was imatinib (Gleevec), an inhibitor of ABL1 as well as the BCR-ABL1 fusion protein  (Figure 2). Several families of kinases, such as tyrosine kinases , cycle-dependent kinases [54,55,56], aurora kinases [57,58], mTOR , and mitogen-activated protein kinases  have already have FDA approved inhibitors and/or inhibitors, which are at different phases of clinical trials. Another approach to inhibit receptor tyrosine kinase signaling is the use of monoclonal antibodies. Trastuzumab (Herceptin), which targets ERBB2, was the first US Food and Drug Administration-approved anti-receptor tyrosine kinase monoclonal antibody . There are also approved antibodies for EGFR , VEGFR2 , and PDGFR .
In summary, this special issue of Cancers is a collection of basic, translational, and clinical research articles as well as reviews, discussing the major impact of protein kinases, signaling pathways regulated by these enzymes and inhibitors of kinases on cancer biology and therapy.
The research of Jonas Cicenas and Egle Zalyte was funded by the Scientific Council of Lithuania (Project #SEN-01/2016). Pascale Gaudet is funded by the SIB Swiss Institute of Bioinformatics, part of the ELIXIR infrastructure.
Conflicts of Interest
The authors declare no conflict of interest.
- Hunter, T.; Cooper, J.A. Protein-tyrosine kinases. Annu. Rev. Biochem. 1985, 54, 897–930. [Google Scholar] [CrossRef] [PubMed]
- Gaudet, P.; Michel, P.A.; Zahn-Zabal, M.; Britan, A.; Cusin, I.; Domagalski, M.; Duek, P.D.; Gateau, A.; Gleizes, A.; Hinard, V.; et al. The nextprot knowledgebase on human proteins: 2017 update. Nucleic Acids Res. 2017, 45, D177–D182. [Google Scholar] [CrossRef] [PubMed]
- Nukaga, S.; Yasuda, H.; Tsuchihara, K.; Hamamoto, J.; Masuzawa, K.; Kawada, I.; Naoki, K.; Matsumoto, S.; Mimaki, S.; Ikemura, S.; et al. Amplification of egfr wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective egfr tyrosine kinase inhibitors. Cancer Res. 2017, 77, 2078–2089. [Google Scholar] [CrossRef] [PubMed]
- Khan, S.A.; Zeng, Z.; Shia, J.; Paty, P.B. Egfr gene amplification and kras mutation predict response to combination targeted therapy in metastatic colorectal cancer. Pathol. Oncol. Res. 2017, 23, 673–677. [Google Scholar] [CrossRef] [PubMed]
- Chang, N.; Lee, H.W.; Lim, J.E.; Jeong, D.E.; Song, H.J.; Kim, S.; Nam, D.H.; Sung, H.H.; Jeong, B.C.; Seo, S.I.; et al. Establishment and antitumor effects of dasatinib and pki-587 in bd-138t, a patient-derived muscle invasive bladder cancer preclinical platform with concomitant egfr amplification and pten deletion. Oncotarget 2016, 7, 51626–51639. [Google Scholar] [CrossRef] [PubMed]
- Zhou, C.; Zhu, L.; Ji, J.; Ding, F.; Wang, C.; Cai, Q.; Yu, Y.; Zhu, Z.; Zhang, J. Egfr high expression, but not kras status, predicts sensitivity of pancreatic cancer cells to nimotuzumab treatment in vivo. Curr. Cancer Drug Targets 2017, 17, 89–97. [Google Scholar] [CrossRef] [PubMed]
- Cho, E.Y.; Choi, Y.L.; Han, J.J.; Kim, K.M.; Oh, Y.L. Expression and amplification of her2, egfr and cyclin d1 in breast cancer: Immunohistochemistry and chromogenic in situ hybridization. Pathol. Int. 2008, 58, 17–25. [Google Scholar] [CrossRef] [PubMed]
- Morey, A.L.; Brown, B.; Farshid, G.; Fox, S.B.; Francis, G.D.; McCue, G.; von Neumann-Cosel, V.; Bilous, M. Determining her2 (erbb2) amplification status in women with breast cancer: Final results from the australian in situ hybridisation program. Pathology 2016, 48, 535–542. [Google Scholar] [CrossRef] [PubMed]
- Hoffmann, M.; Pasch, S.; Schamberger, T.; Maneck, M.; Mohlendick, B.; Schumacher, S.; Brockhoff, G.; Knoefel, W.T.; Izbicki, J.; Polzer, B.; et al. Diagnostic pathology of early systemic cancer: Erbb2 gene amplification in single disseminated cancer cells determines patient survival in operable esophageal cancer. Int. J. Cancer 2017, 142, 833–843. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.K.; Yang, B.F.; Yun, T.; Zhu, C.Y.; Li, C.Y.; Jiang, B.; Wang, G.P.; Wang, S.N.; Li, Y.Y.; Zhu, M.L. Methods and significance of the combined detection of her2 gene amplification and chemosensitivity in gastric cancer. Cancer Biomark. 2017, 21, 439–447. [Google Scholar] [CrossRef] [PubMed]
- Han, C.P.; Hsu, J.D.; Yao, C.C.; Lee, M.Y.; Ruan, A.; Tyan, Y.S.; Yang, S.F.; Chiang, H. Her2 gene amplification in primary mucinous ovarian cancer: A potential therapeutic target. Histopathology 2010, 57, 763–764. [Google Scholar] [CrossRef] [PubMed]
- Xu, C.W.; Wang, W.X.; Wu, M.J.; Zhu, Y.C.; Zhuang, W.; Lin, G.; Du, K.Q.; Huang, Y.J.; Chen, Y.P.; Chen, G.; et al. Comparison of the c-met gene amplification between primary tumor and metastatic lymph nodes in non-small cell lung cancer. Thorac. Cancer 2017, 8, 417–422. [Google Scholar] [CrossRef] [PubMed]
- An, X.; Wang, F.; Shao, Q.; Wang, F.H.; Wang, Z.Q.; Wang, Z.Q.; Chen, C.; Li, C.; Luo, H.Y.; Zhang, D.S.; et al. Met amplification is not rare and predicts unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy. Cancer 2014, 120, 675–682. [Google Scholar] [CrossRef] [PubMed]
- Di Renzo, M.F.; Olivero, M.; Giacomini, A.; Porte, H.; Chastre, E.; Mirossay, L.; Nordlinger, B.; Bretti, S.; Bottardi, S.; Giordano, S.; et al. Overexpression and amplification of the met/hgf receptor gene during the progression of colorectal cancer. Clin. Cancer Res. 1995, 1, 147–154. [Google Scholar] [PubMed]
- Miwa, W.; Yasuda, J.; Murakami, Y.; Yashima, K.; Sugano, K.; Sekine, T.; Kono, A.; Egawa, S.; Yamaguchi, K.; Hayashizaki, Y.; et al. Isolation of DNA sequences amplified at chromosome 19q13.1-q13.2 including the akt2 locus in human pancreatic cancer. Biochem. Biophys. Res. Commun. 1996, 225, 968–974. [Google Scholar] [CrossRef] [PubMed]
- Cheng, J.Q.; Godwin, A.K.; Bellacosa, A.; Taguchi, T.; Franke, T.F.; Hamilton, T.C.; Tsichlis, P.N.; Testa, J.R. Akt2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl. Acad. Sci. USA 1992, 89, 9267–9271. [Google Scholar] [CrossRef] [PubMed]
- Alterio, D.; Marvaso, G.; Maffini, F.; Gandini, S.; Chiocca, S.; Ferrari, A.; Preda, L.; Rocca, M.C.; Lepanto, D.; Fodor, C.; et al. Role of egfr as prognostic factor in head and neck cancer patients treated with surgery and postoperative radiotherapy: Proposal of a new approach behind the egfr overexpression. Med. Oncol. 2017, 34, 107. [Google Scholar] [CrossRef] [PubMed]
- Curigliano, G.; Viale, G.; Bagnardi, V.; Fumagalli, L.; Locatelli, M.; Rotmensz, N.; Ghisini, R.; Colleoni, M.; Munzone, E.; Veronesi, P.; et al. Clinical relevance of her2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J. Clin. Oncol. 2009, 27, 5693–5699. [Google Scholar] [CrossRef] [PubMed]
- Hou, F.; Yuan, W.; Huang, J.; Qian, L.; Chen, Z.; Ge, J.; Wu, S.; Chen, J.; Wang, J.; Chen, Z. Overexpression of epha2 correlates with epithelial-mesenchymal transition-related proteins in gastric cancer and their prognostic importance for postoperative patients. Med. Oncol. 2012, 29, 2691–2700. [Google Scholar] [CrossRef] [PubMed]
- Archewa, P.; Pata, S.; Chotjumlong, P.; Supanchart, C.; Krisanaprakornkit, S.; Iamaroon, A. Akt2 and p-akt overexpression in oral cancer cells is due to a reduced rate of protein degradation. J. Investig. Clin. Dent. 2017, 8, e12194. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J. The potential role of the egfr/erbb2 heterodimer in breast cancer. Expert Opin. Ther. Pat. 2007, 17, 6. [Google Scholar] [CrossRef]
- Kanematsu, T.; Yano, S.; Uehara, H.; Bando, Y.; Sone, S. Phosphorylation, but not overexpression, of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients. Oncol. Res. 2003, 13, 289–298. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Urban, P.; Kung, W.; Vuaroqueaux, V.; Labuhn, M.; Wight, E.; Eppenberger, U.; Eppenberger-Castori, S. Phosphorylation of tyrosine 1248-erbb2 measured by chemiluminescence-linked immunoassay is an independent predictor of poor prognosis in primary breast cancer patients. Eur. J. Cancer 2006, 42, 636–645. [Google Scholar] [CrossRef] [PubMed]
- DiGiovanna, M.P.; Stern, D.F.; Edgerton, S.M.; Whalen, S.G.; Moore, D., 2nd; Thor, A.D. Relationship of epidermal growth factor receptor expression to erbb-2 signaling activity and prognosis in breast cancer patients. J. Clin. Oncol. 2005, 23, 1152–1160. [Google Scholar] [CrossRef] [PubMed]
- Milde-Langosch, K.; Bamberger, A.M.; Rieck, G.; Grund, D.; Hemminger, G.; Muller, V.; Loning, T. Expression and prognostic relevance of activated extracellular-regulated kinases (erk1/2) in breast cancer. Br. J. Cancer 2005, 92, 2206–2215. [Google Scholar] [CrossRef] [PubMed]
- Kitajima, S.; Kudo, Y.; Ogawa, I.; Tatsuka, M.; Kawai, H.; Pagano, M.; Takata, T. Constitutive phosphorylation of aurora-a on ser51 induces its stabilization and consequent overexpression in cancer. PLoS ONE 2007, 2, e944. [Google Scholar] [CrossRef] [PubMed]
- Fan, X.J.; Wan, X.B.; Fu, X.H.; Wu, P.H.; Chen, D.K.; Wang, P.N.; Jiang, L.; Wang, D.H.; Chen, Z.T.; Huang, Y.; et al. Phosphorylated p38, a negative prognostic biomarker, complements tnm staging prognostication in colorectal cancer. Tumour Biol. 2014, 35, 10487–10495. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Urban, P.; Vuaroqueaux, V.; Labuhn, M.; Kung, W.; Wight, E.; Mayhew, M.; Eppenberger, U.; Eppenberger-Castori, S. Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing erbb-2. Breast Cancer Res. 2005, 7, R394–R401. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Cicenas, J. The potential role of akt phosphorylation in human cancers. Int. J. Biol. Markers 2008, 23, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Kung, W.; Eppenberger, U.; Eppenberger-Castori, S. Increased level of phosphorylated shca measured by chemiluminescence-linked immunoassay is a predictor of good prognosis in primary breast cancer expressing low levels of estrogen receptor. Cancers 2010, 2, 153–164. [Google Scholar] [CrossRef] [PubMed]
- Xia, W.; Chen, J.S.; Zhou, X.; Sun, P.R.; Lee, D.F.; Liao, Y.; Zhou, B.P.; Hung, M.C. Phosphorylation/cytoplasmic localization of p21cip1/waf1 is associated with her2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin. Cancer Res. 2004, 10, 3815–3824. [Google Scholar] [CrossRef] [PubMed]
- Clarke, R.B. P27kip1 phosphorylation by pkb/akt leads to poor breast cancer prognosis. Breast Cancer Res. 2003, 5, 162–163. [Google Scholar] [CrossRef] [PubMed]
- Willder, J.M.; Heng, S.J.; McCall, P.; Adams, C.E.; Tannahill, C.; Fyffe, G.; Seywright, M.; Horgan, P.G.; Leung, H.Y.; Underwood, M.A.; et al. Androgen receptor phosphorylation at serine 515 by cdk1 predicts biochemical relapse in prostate cancer patients. Br. J. Cancer 2013, 108, 139–148. [Google Scholar] [CrossRef] [PubMed]
- Derenzini, M.; Montanaro, L.; Vici, M.; Barbieri, S.; Ceccarelli, C.; Santini, D.; Taffurelli, M.; Martinelli, G.N.; Trere, D. Relationship between the rb1 mrna level and the expression of phosphorylated rb protein in human breast cancers: Their relevance in cell proliferation activity and patient clinical outcome. Histol. Histopathol. 2007, 22, 505–513. [Google Scholar] [PubMed]
- Davies, H.; Bignell, G.R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M.J.; Bottomley, W.; et al. Mutations of the braf gene in human cancer. Nature 2002, 417, 949–954. [Google Scholar] [CrossRef] [PubMed]
- Ritterhouse, L.L.; Barletta, J.A. Braf v600e mutation-specific antibody: A review. Semin. Diagn. Pathol. 2015, 32, 400–408. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Tamosaitis, L.; Kvederaviciute, K.; Tarvydas, R.; Staniute, G.; Kalyan, K.; Meskinyte-Kausiliene, E.; Stankevicius, V.; Valius, M. Kras, nras and braf mutations in colorectal cancer and melanoma. Med. Oncol. 2017, 34, 26. [Google Scholar] [CrossRef] [PubMed]
- Elisei, R.; Ugolini, C.; Viola, D.; Lupi, C.; Biagini, A.; Giannini, R.; Romei, C.; Miccoli, P.; Pinchera, A.; Basolo, F. Braf(v600e) mutation and outcome of patients with papillary thyroid carcinoma: A 15-year median follow-up study. J. Clin. Endocrinol. Metab. 2008, 93, 3943–3949. [Google Scholar] [CrossRef] [PubMed]
- Rothschild, S.I. Targeted therapies in non-small cell lung cancer-beyond egfr and alk. Cancers 2015, 7, 930–949. [Google Scholar] [CrossRef] [PubMed]
- Yan, L.; Zou, L.; Zhao, W.; Wang, Y.; Liu, B.; Yao, H.; Yu, H. Clinicopathological significance of c-kit mutation in gastrointestinal stromal tumors: A systematic review and meta-analysis. Sci. Rep. 2015, 5, 13718. [Google Scholar] [CrossRef] [PubMed]
- Inal, C.; Yilmaz, E.; Piperdi, B.; Perez-Soler, R.; Cheng, H. Emerging treatment for advanced lung cancer with egfr mutation. Expert Opin. Emerg. Drugs 2015, 20, 597–612. [Google Scholar] [CrossRef] [PubMed]
- Kiyoi, H.; Naoe, T. Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with flt3 mutation. Int. J. Hematol. 2006, 83, 301–308. [Google Scholar] [CrossRef] [PubMed]
- Melo, J.V. Bcr-abl gene variants. Baillieres Clin. Haematol. 1997, 10, 203–222. [Google Scholar] [CrossRef]
- Talpaz, M.; Shah, N.P.; Kantarjian, H.; Donato, N.; Nicoll, J.; Paquette, R.; Cortes, J.; O'Brien, S.; Nicaise, C.; Bleickardt, E.; et al. Dasatinib in imatinib-resistant philadelphia chromosome-positive leukemias. N. Engl. J. Med. 2006, 354, 2531–2541. [Google Scholar] [CrossRef] [PubMed]
- Sabir, S.R.; Yeoh, S.; Jackson, G.; Bayliss, R. Eml4-alk variants: Biological and molecular properties, and the implications for patients. Cancers 2017, 9, 118. [Google Scholar] [CrossRef] [PubMed]
- Gotlib, J.; Cools, J. Five years since the discovery of fip1l1-pdgfra: What we have learned about the fusion and other molecularly defined eosinophilias. Leukemia 2008, 22, 1999–2010. [Google Scholar] [CrossRef] [PubMed]
- Griseri, P.; Garrone, O.; Lo Sardo, A.; Monteverde, M.; Rusmini, M.; Tonissi, F.; Merlano, M.; Bruzzi, P.; Lo Nigro, C.; Ceccherini, I. Genetic and epigenetic factors affect ret gene expression in breast cancer cell lines and influence survival in patients. Oncotarget 2016, 7, 26465–26479. [Google Scholar] [CrossRef] [PubMed]
- Haag, T.; Herkt, C.E.; Walesch, S.K.; Richter, A.M.; Dammann, R.H. The apoptosis associated tyrosine kinase gene is frequently hypermethylated in human cancer and is regulated by epigenetic mechanisms. Genes Cancer 2014, 5, 365–374. [Google Scholar] [PubMed]
- Fu, D.Y.; Wang, Z.M.; Wang, B.L.; Chen, L.; Yang, W.T.; Shen, Z.Z.; Huang, W.; Shao, Z.M. Frequent epigenetic inactivation of the receptor tyrosine kinase epha5 by promoter methylation in human breast cancer. Hum. Pathol. 2010, 41, 48–58. [Google Scholar] [CrossRef] [PubMed]
- Kim, D.S.; Kim, M.J.; Lee, J.Y.; Lee, S.M.; Choi, J.E.; Lee, S.Y.; Park, J.Y. Epigenetic inactivation of checkpoint kinase 2 gene in non-small cell lung cancer and its relationship with clinicopathological features. Lung Cancer 2009, 65, 247–250. [Google Scholar] [CrossRef] [PubMed]
- Kim, M.; Jang, H.R.; Kim, J.H.; Noh, S.M.; Song, K.S.; Cho, J.S.; Jeong, H.Y.; Norman, J.C.; Caswell, P.T.; Kang, G.H.; et al. Epigenetic inactivation of protein kinase d1 in gastric cancer and its role in gastric cancer cell migration and invasion. Carcinogenesis 2008, 29, 629–637. [Google Scholar] [CrossRef] [PubMed]
- Druker, B.J. Sti571 (gleevec) as a paradigm for cancer therapy. Trends Mol. Med. 2002, 8, S14–S18. [Google Scholar] [CrossRef]
- Gharwan, H.; Groninger, H. Kinase inhibitors and monoclonal antibodies in oncology: Clinical implications. Nat. Rev. Clin. Oncol. 2016, 13, 209–227. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Valius, M. The cdk inhibitors in cancer research and therapy. J. Cancer Res. Clin. Oncol. 2011, 137, 1409–1418. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Kalyan, K.; Sorokinas, A.; Stankunas, E.; Levy, J.; Meskinyte, I.; Stankevicius, V.; Kaupinis, A.; Valius, M. Roscovitine in cancer and other diseases. Ann. Transl. Med. 2015, 3, 135. [Google Scholar] [PubMed]
- Cicenas, J.; Kalyan, K.; Sorokinas, A.; Jatulyte, A.; Valiunas, D.; Kaupinis, A.; Valius, M. Highlights of the latest advances in research on cdk inhibitors. Cancers 2014, 6, 2224–2242. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J. The aurora kinase inhibitors in cancer research and therapy. J. Cancer Res. Clin. Oncol. 2016, 142, 1995–2012. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J.; Cicenas, E. Multi-kinase inhibitors, aurks and cancer. Med. Oncol. 2016, 33, 43. [Google Scholar] [CrossRef] [PubMed]
- Xie, J.; Wang, X.; Proud, C.G. Mtor inhibitors in cancer therapy. F1000Res 2016. [Google Scholar] [CrossRef] [PubMed]
- Cicenas, J. Jnk inhibitors: Is there a future? MAP Kinases 2015, 4, 7. [Google Scholar] [CrossRef]
- Hudis, C.A. Trastuzumab--mechanism of action and use in clinical practice. N. Engl. J. Med. 2007, 357, 39–51. [Google Scholar] [CrossRef] [PubMed]
- Yang, B.B.; Lum, P.; Chen, A.; Arends, R.; Roskos, L.; Smith, B.; Perez Ruixo, J.J. Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab. Clin. Pharmacokinet. 2010, 49, 729–740. [Google Scholar] [CrossRef] [PubMed]
- Krupitskaya, Y.; Wakelee, H.A. Ramucirumab, a fully human mab to the transmembrane signaling tyrosine kinase vegfr-2 for the potential treatment of cancer. Curr. Opin. Investig. Drugs 2009, 10, 597–605. [Google Scholar] [PubMed]
- Vincenzi, B.; Badalamenti, G.; Napolitano, A.; Spalato Ceruso, M.; Pantano, F.; Grignani, G.; Russo, A.; Santini, D.; Aglietta, M.; Tonini, G. Olaratumab: Pdgfr-alpha inhibition as a novel tool in the treatment of advanced soft tissue sarcomas. Crit. Rev. Oncol. Hematol. 2017, 118, 1–6. [Google Scholar] [CrossRef] [PubMed]
Figure 1. The neXtProt function page for MAPK13 (https://www.nextprot.org/entry/NX_O15264/).
Figure 2. Imatinib (Gleevec) is the first FDA approved kinase inhibitor. Approved for the treatment of KIT+ GIST and Ph+ CML.
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