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Review (Published online: 29-01-2016)

15. Recent developments in receptor tyrosine kinases targeted anticancer therapy - Samir H. Raval, Ratn D. Singh, Dilip V. Joshi, Hitesh B. Patel and Shailesh K. Mody

Veterinary World, 9(1): 80-90



   doi: 10.14202/vetworld.2016.80-90



Samir H. Raval: Department of Veterinary Pathology, College of Veterinary Science and Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Banaskantha - 385 506, Gujarat, India;

Ratn D. Singh: Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Banaskantha - 385 506, Gujarat, India;

Dilip V. Joshi: Department of Veterinary Pathology, College of Veterinary Science and Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Banaskantha - 385 506, Gujarat, India;

Hitesh B. Patel: Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Banaskantha - 385 506, Gujarat, India;

Shailesh K. Mody: Department of Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, Banaskantha - 385 506, Gujarat, India;


Received: 04-09-2015, Revised: 04-12-2015, Accepted: 09-12-2015, Published online: 29-01-2016


Corresponding author: Samir H. Raval, e-mail:

Citation: Raval SH, Singh RD, Joshi DV, Patel HB, Mody SK (2016) Recent developments in receptor tyrosine kinases targeted anticancer therapy, Veterinary World 9(1): 80-90.

Novel concepts and understanding of receptors lead to discoveries and optimization of many small molecules and antibodies as anti-cancerous drugs. Receptor tyrosine kinases (RTKs) are such a promising class of receptors under the investigation in past three decades. RTKs are one of the essential mediators of cell signaling mechanism for various cellular processes. Transformations such as overexpression, dysregulation, or mutations of RTKs may result into malignancy, and thus are an important target for anticancer therapy. Numerous subfamilies of RTKs, such as epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptors, insulin-like growth factor receptor, and hepatocyte growth factor receptor, have been being investigated in recent years as target for anticancer therapy. The present review focuses several small molecules drugs as well as monoclonal antibodies targeting aforesaid subfamilies either approved or under investigation to treat the various cancers.

Keywords: cancer, monoclonal antibodies, small molecule drugs, receptor tyrosine kinases, targeted therapy.

1. Gschwind, A., Fischer, O.M. and Ullrich, A. (2004) The discovery of receptor tyrosine kinases: Targets for cancer therapy. Nat. Rev. Cancer, 4(5): 361-370.
2. Lemmon, M.A. and Schlessinger, J. (2010) Cell signaling by receptor tyrosine kinases. Cell, 141(7): 1117-1134.
PMid:20602996 PMCid:PMC2914105
3. Arora, A. and Scholar, E.M. (2005) Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther., 315(3): 971-979.
4. Li, E. and Hristova, K. (2006) Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies. Biochemistry, 45(20): 6241-6251.
PMid:16700535 PMCid:PMC4301406
5. Paul, M.K. and Mukhopadhyay, A.K. (2004) Tyrosine kinase – Role and significance in Cancer. Int. J. Med. Sci., 1(283): 101-115.
6. Pytel, D., Sliwinski, T., Poplawski, T., Ferriola, D. and Majsterek, I. (2009) Tyrosine kinase blockers: New hope for successful cancer therapy. Anticancer. Agents Med. Chem., 9: 66-76.
7. Porter, A.C. and Vaillancourt, R.R. (1998) Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene, 17(11): 1343-1352.
8. Wu, H., Chang, D. and Huang, C. (2006) Targeted-therapy for cancer. J. Cancer Mol., 2: 57-66.
9. Urruticoechea, A., Alemany, R., Balart, J., Villanueva, A., Vi-als, F. and Capellá, G. (2010) Recent advances in cancer therapy: An overview. Curr. Pharm. Des., 16: 3-10.
10. Grassot, J. (2003) RTKdb: Database of receptor tyrosine kinase. Nuc. Acids Res., 31(1): 353-358.
11. Bari, S.B., Adhikari, S. and Surana, S.J. (2012) Tyrosine kinase receptor inhibitors: A new target for anticancer drug development. J. Pharm. Sci. Technol., 1(2): 36-45.
12. Eckstein, N., Röper, L., Haas, B., Potthast, H., Hermes, U., Unkrig, C., Naumann-Winter, F. and Enzmann, H. (2014) Clinical pharmacology of tyrosine kinase inhibitors becoming generic drugs: The regulatory perspective. J. Exp. Clin. Cancer Res., 33(1): 15.
13. Levitzki, A. and Klein, S. (2010) Signal transduction therapy of cancer. Mol. Aspects Med., 31(4): 287-329.
14. Maruyama, I.N. (2014) Mechanisms of activation of receptor tyrosine kinases: Monomers or dimers. Cells, 3: 304-330.
PMid:24758840 PMCid:PMC4092861
15. Lodish, H., Berk, A., Zipursky, S.L., Matsudaira, P., Baltimore, D. and Darnell, J. (2000) Molecular Cell Biology. 4th ed. W. H. Freeman, New York.
16. Haj, F.G., Markova, B., Klaman, L.D., Bohmer, F.D. and Neel, B.G. (2003) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J. Biol. Chem., 278(2): 739-744.
17. Ostman, A., Hellberg, C. and Böhmer, F.D. (2006) Protein-tyrosine phosphatases and cancer. Nat. Rev. Cancer, 6(4): 307-320.
18. Schmidt-Arras, D.E., Böhmer, A., Markova, B., Choudhary, C., Serve, H. and Böhmer, F.D. (2005) Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases. Mol. Cell. Biol., 25(9): 3690-3703.
PMid:15831474 PMCid:PMC1084288
19. Schmidt, M.H.H., Furnari, F.B., Cavenee, W.K. and Bögler, O. (2003) Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization. Proc. Natl. Acad. Sci. U.S.A., 100(11): 6505-6510.
PMid:12734385 PMCid:PMC164476
20. Goh, L.K. and Sorkin, A. (2013) Endocytosis of receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol., 5(5): 1-17.
21. Wiley, H.S. and Burke, P.M. (2001) Regulation of receptor tyrosine kinase signaling by endocytic trafficking. Traffic, 2(1): 12-18.
22. Harmey, J.H., Dimitriadis, E., Kay, E., Redmond, H.P. and Bouchier-Hayes, D. (1998) Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann. Surg. Oncol., 5(3): 271-278.
23. Molhoek, K.R., Shada, A.L., Smolkin, M., Chowbina, S., Papin, J., Brautigan, D.L. and Slingluff, C.L. (2011) Comprehensive analysis of receptor tyrosine kinase activation in human melanomas reveals autocrine signaling through IGF-1R. Melanoma Res., 21(4): 274-284.
PMid:21654344 PMCid:PMC3131461
24. Hollmén, M., Määttä, J.A., Bald, L., Sliwkowski, M.X. and Elenius, K. (2009) Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms. Oncogene, 28(10): 1309-1319.
25. Greulich, H., Kaplan, B., Mertins, P., Chen, T.H., Tanaka, K.E., Yun, C.H., Zhang, X., Lee, S.H., Cho, J., Ambrogio, L., Liao, R., Imielinski, M., Banerji, S., Berger, A.H., Lawrence, M.S., Zhang, J., Pho, N.H., Walker, S.R., Winckler, W., Getz, G., Frank, D., Hahn, W.C., Eck, M.J., Mani, D.R., Jaffe, J.D., Carr, S.A., Wong, K.K. and Meyerson, M. (2012) Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc. Natl. Acad. Sci., 109(36): 14476-14481.
PMid:22908275 PMCid:PMC3437859
26. Ozer, B.H., Wiepz, G.J. and Bertics, P.J. (2010) Activity and cellular localization of an oncogenic glioblastoma multiforme-associated EGF receptor mutant possessing a duplicated kinase domain. Oncogene, 29(6): 855-864.
PMid:19915609 PMCid:PMC2820599
27. Szerlip, N.J., Pedraza, A., Chakravarty, D., Azim, M., McGuire, J., Fang, Y., Ozawa, T., Holland, E.C., Huse, J.T., Jhanwar, S., Leversha, M.A., Mikkelsen, T. and Brennan, C.W. (2012) Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc. Natl. Acad. Sci., 109(8): 3041-3046.
PMid:22323597 PMCid:PMC3286976
28. Bhargava, R., Gerald, W.L., Li, A.R., Pan, Q., Lal, P., Ladanyi, M. and Chen, B. (2005) EGFR gene amplification in breast cancer: Correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod. Pathol., 18(8): 1027-1033.
29. Sholl, L.M., Yeap, B.Y., Iafrate, A.J., Holmes-Tisch, A.J., Chou, Y.P., Wu, M.T., Goan, Y.G., Su, L., Benedettini, E., Yu, J., Loda, M., Jänne, P.A., Christiani, D.C. and Chirieac, L. R. (2009) Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers. Cancer Res., 69(21): 8341-8348.
PMid:19826035 PMCid:PMC2783286
30. Gunby, R.H., Sala, E., Tartari, C.J., Puttini, M., Gambacorti-Passerini, C. and Mologni, L. (2007) Oncogenic fusion tyrosine kinases as molecular targets for anti-cancer therapy. Anticancer. Agents Med. Chem., 7(6): 594-611.
31. Shaw, A.T., Hsu, P.P., Awad, M.M. and Engelman, J.A. (2013) Tyrosine kinase gene rearrangements in epithelial malignancies. Nat. Rev. Cancer, 13(11): 772-787.
PMid:24132104 PMCid:PMC3902129
32. Gerber, D.E. (2008) Targeted therapies: A new generation of cancer treatments. Am. Fam. Phys., 77(3): 311-319.
33. Joo, W.D., Visintin, I. and Mor, G. (2013) Targeted cancer therapy - Are the days of systemic chemotherapy numbered? Maturitas, 76(4): 308-314.
PMid:24128673 PMCid:PMC4610026
34. Giaccone, G. (2004) The role of gefitinib in lung cancer treatment. Clin. Cancer Res., 10: 4233s-4237s.
35. Gridelli, C., Bareschino, M.A., Schettino, C., Rossi, A., Maione, P. and Ciardiello, F. (2007) Erlotinibin non-small cell lung cancer treatment: Current status and future development. Oncologist, 12: 840-849.
36. Bilancia, D., Rosati, G., Dinota, A., Germano, D., Romano, R. and Manzione, L. (2007) Lapatinib in breast cancer. Ann. Oncol., 18(6): 26-30.
37. Nelson, V., Ziehr, J., Agulnik, M. and Johnson, M. (2013) Afatinib: Emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco. Targets. Ther., 6: 135-143.
PMid:23493883 PMCid:PMC3594037
38. Martin, P., Kelly, C.M.A. and Carney, D. (2006) Epidermal growth factor receptor-targeted agents for lung cancer. Cancer Control, 13(2): 129-140.
39. Tiseo, M., Bartolotti, M., Gelsomino, F. and Bordi, P. (2010) Emerging role of gefitinib in the treatment of non-small-cell lung cancer (NSCLC). Drug Des. Dev. Ther., 4: 81-98.
PMid:20531963 PMCid:PMC2880339
40. Scott, A.M., Wolchok, J.D. and Old, L.J. (2012) Antibody therapy of cancer. Nat. Rev. Cancer, 12(4): 278-287.
41. Carter, P. (2001) Improving the efficacy of antibody-based cancer therapies. Nat. Rev. Cancer, 1(2): 118-129.
42. Pierotti, M.A., Negri, T., Tamborini, E., Perrone, F., Pricl, S. and Pilotti, S. (2010) Targeted therapies: The rare cancer paradigm. Mol. Oncol., 4(1): 19-37.
43. Yarden, Y. and Sliwkowski, M.X. (2001) Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol., 2: 127-137.
44. Dziadziuszko, R. and Jassem, J. (2012) Epidermal growth factor receptor (EGFR) inhibitors and derived treatments. Ann. Oncol., 23 10 Suppl: x193-x196.
45. Sasaki, T., Hiroki, K. and Yamashita, Y. (2013) The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Biomed. Res. Int., 2013: 1-8.
PMid:23986907 PMCid:PMC3748428
46. Mendelsohn, J. and Baselga, J. (2000) The EGF receptor family as targets for cancer therapy. Oncogene, 19: 6550-6565.
47. Hynes, N.E. and Lane, H.A. (2005) ERBB receptors and cancer: The complexity of targeted inhibitors. Nat. Rev. Cancer, 5: 341-354.
48. Normanno, N., De Luca, A., Bianco, C., Strizzi, L., Mancino, M., Maiello, M.R., Carotenuto, A., De Feo, G., Caponigro, F. and Salomon, D.S. (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 366: 2-16.
49. Spector, N., Xia, W., El-Hariry, I., Yarden, Y. and Bacus, S. (2007) HER2 therapy. Small molecule HER-2 tyrosine kinase inhibitors. Breast Cancer Res., 9: 205.
50. Yarom, N. and Jonker, D.J. (2011) The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov. Med., 11(57): 95-105.
51. Jiang, N., Saba, N.F. and Chen, Z.G. (2012) Advances in targeting HER3 as an anticancer therapy. Chemother. Res. Pract., 2012: 1-9.
PMid:23198146 PMCid:PMC3502787
52. Biswas, B. (2015) Erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer in the era of personalized medicine. J. Clin. Oncol., 33: 524-524.
53. Lee, S.M., Lewanski, C.R., Counsell, N., Ottensmeier, C., Bates, A., Patel, N., Wadsworth, C., Ngai, Y., Hackshaw, A. and Faivre-Finn, C. (2014) Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J. Natl. Cancer Inst., 106(7): pii: dju151.
54. Coudert, B., Ciuleanu, T., Park, K., Wu, Y.L., Giaccone, G., Brugger, W., Gopalakrishna, P. and Cappuzzo, F. (2012) Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Ann. Oncol., 23: 388-394.
55. Gemmete, J.J. and Mukherji, S.K. (2011) Trastuzumab (Herceptin). Am. J. Neuroradiol., 32: 1373-1374.
56. Bang, Y.J., Van Cutsem, E., Feyereislova, A., Chung, H.C., Shen, L., Sawaki, A., Lordick, F., Ohtsu, A., Omuro, Y., Satoh, T., Aprile, G., Kulikov, E., Hill, J., Lehle, M., Rüschoff, J. and Kang, Y.K. (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet, 376(9742): 687-697.
57. Hansen, A.R. and Siu, L.L. (2013) Epidermal growth factor receptor targeting in head and neck cancer: Have we been just skimming the surface? J. Clin. Oncol., 31(11): 1381-1383.
58. Hitt, R., Irigoyen, A., Cortes-Funes, H., Grau, J.J., García-Sáenz, J.A. and Cruz-Hernandez, J.J. (2012) Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann. Oncol., 23: 1016-1022.
59. Vermorken, J.B. and Specenier, P. (2010) Optimal treatment for recurrent/metastatic head and neck cancer. Ann. Oncol., 21 Suppl 7: 252-261.
60. Van Cutsem, E., Köhne, C.H., Hitre, E., Zaluski, J., Chang Chien, C.R., Makhson, A., D'Haens, G., Pintér, T., Lim, R., Bodoky, G., Roh, J.K., Folprecht, G., Ruff, P., Stroh, C., Tejpar, S., Schlichting, M., Nippgen, J. and Rougier, P. (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med., 360(14): 1408-1417.
61. Gemmete, J.J. and Mukherji, S.K. (2011) Panitumumab (Vectibix). Am. J. Neuroradiol., 32(6): 1002-1003.
62. Olsson, A.K., Dimberg, A., Kreuger, J. and Claesson-Welsh, L. (2006) VEGF receptor signalling - in control of vascular function. Nat. Rev. Mol. Cell Biol., 7(5): 359-371.
63. Ferrara, N., Gerber, H.P. and LeCouter, J. (2003) The biology of VEGF and its receptors. Nat. Med., 9: 669-676.
64. Takahashi, H. and Shibuya, M. (2005) The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin. Sci. (Lond), 109: 227-241.
65. Hoeben, A., Landuyt, B., Highley, M.S., Wildiers, H., Van Oosterom, A.T. and De Bruijn, E.A. (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol. Rev., 56(4): 549-580.
66. Roberts, E., Cossigny, D.A.F. and Quan, G.M.Y. (2013) The role of vascular endothelial growth factor in metastatic prostate cancer to the skeleton. Prostate Cancer, 2013: 1-8.
PMid:24396604 PMCid:PMC3874956
67. Shibuya, M. (2001) Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). Int. J. Biochem. Cell Biol., 33(4): 409-420.
68. Iljin, K., Karkkainen, M.J., Lawrence, E.C., Kimak, M.A., Uutela, M., Taipale, J., Pajusola, K., Alhonen, L., Halmekytö, M., Finegold, D.N., Ferrell, R.E. and Alitalo, K. (2001) VEGFR3 gene structure, regulatory region, and sequence polymorphisms. FASEB J., 15(6): 1028-1036.
69. Rosen, L.S. (2005) VEGF-targeted therapy: Therapeutic potential and recent advances. Oncologist, 10(6): 382-391.
70. Folkman, J. (1990) What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst., 82(1): 4-6.
71. Ellis, L.M. and Hicklin, D.J. (2008) VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat. Rev. Cancer, 8(8): 579-591.
72. Rosen, L.S. (2002) Clinical experience with angiogenesis signaling inhibitors: Focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control., 9 Suppl 2: 36-44.
73. Jost, L.M., Gschwind, H.P., Jalava, T., Wang, Y., Guenther, C., Souppart, C., Rottmann, A., Denner, K., Waldmeier, F., Gross, G., Masson, E. and Laurent, D. (2006) Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients. Drug Metab. Dispos., 34(11): 1817-1828.
74. Morgan, B., Thomas, A.L., Drevs, J., Hennig, J., Buchert, M., Jivan, A., Horsfield, M.A., Mross, K., Ball, H.A., Lee, L., Mietlowski, W., Fuxuis, S., Unger, C., O'Byrne, K., Henry, A., Cherryman, G.R., Laurent, D., Dugan, M., Marmé, D. and Steward, W.P. (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liv. J. Clin. Oncol., 21(21): 3955-3964.
75. Dragovich, T., Laheru, D., Dayyani, F., Bolejack, V., Smith, L., Seng, J., Burris, H., Rosen, P., Hidalgo, M., Ritch, P., Baker, A.F., Raghunand, N., Crowley, J. and Von Hoff, D.D. (2014) Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother. Pharmacol., 74(2): 379-387.
PMid:24939212 PMCid:PMC4461053
76. Sobrero, A.F. and Bruzzi, P. (2011) Vatalanib in advanced colorectal cancer: Two studies with identical results. J. Clin. Oncol., 29(15): 1938-1940.
77. Giatromanolaki, A., Koukourakis, M.I., Sivridis, E., Gatter, K.C., Trarbach, T., Folprecht, G., Shi, M.M., Lebwohl, D., Jalava, T., Laurent, D., Meinhardt, G. and Harris, A.L. (2012) Vascular density analysis in colorectal cancer patients treated with vatalanib (PTK787/ZK222584) in the randomised confirm trials. Br. J. Cancer, 107(7): 1044-1050.
PMid:22910317 PMCid:PMC3461163
78. Gauler, T.C., Besse, B., Mauguen, A., Meric, J.B., Gounant, V., Fischer, B., Overbeck, T.R., Krissel, H., Laurent, D., Tiainen, M., Commo, F., Soria, J.C. and Eberhardt, W.E.E. (2012) Phase II trial of ptk787/zk 222584 (vatalanib) administered orally once-daily or in two divided daily doses as second-line monotherapy in relapsed or progressing patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Ann. Oncol., 23(3): 678-687.
79. Bachelier, R., Confavreux, C.B., Peyruchaud, O., Croset, M., Goehrig, D., Van Der Pluijm, G. and Clézardin, P. (2014) Combination of anti-angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis. Int. J. Cancer, 135(6): 1319-1329.
80. Motzer, R.J., Hutson, T.E., Tomczak, P., Michaelson, M.D., Bukowski, R.M., Rixe, O., Oudard, S., Negrier, S., Szczylik, C., Kim, S.T., Chen, I., Bycott, P.W., Baum, C.M. and Figlin, R.A. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med., 356(2): 115-124.
81. Porta, C., Paglino, C. and Grünwald, V. (2014) Sunitinib re-challenge in advanced renal-cell carcinoma. Br. J. Cancer, 111(6): 1047-1053.
PMid:24800947 PMCid:PMC4453836
82. Younus, J., Verma, S., Franek, J. and Coakley, N. (2010) Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate-resistant patients: Recommendations and evidence. Curr. Oncol., 17(4): 4-10.
83. Mukherji, S.K. (2010) Bevacizumab (Avastin). AJNR. Am. J. Neuroradiol., 31: 235-236.
84. Loupakis, F., Cremolini, C., Masi, G., Lonardi, S., Zagonel, V., Salvatore, L., Cortesi, E., Tomasello, G., Ronzoni, M., Spadi, R., Zaniboni, A., Tonini, G., Buonadonna, A., Amoroso, D., Chiara, S., Carlomagno, C., Boni, C., Allegrini, G., Boni, L. and Falcone, A. (2014) Initial therapy with foleoxiri and bevacizumab for metastatic colorectal cancer. N. Engl. J. Med., 371(17): 1609-1618.
85. McCormack, P.L. and Keam, S.J. (2008) Bevacizumab: A review of its use in metastatic colorectal cancer. Drugs, 68(4): 487-506.
86. Barlesi, F., Scherpereel, A., Gorbunova, V., Gervais, R., Vikström, A., Chouaid, C., Chella, A., Kim, J.H., Ahn, M.J., Reck, M., Pazzola, A., Kim, H.T., Aerts, J.G., Morando, C., Loundou, A., Groen, H.J.M. and Rittmeyer, A. (2014) Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: Updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann. Oncol., 25(5): 1044-1052.
87. Vu, T., Sliwkowski, M.X. and Claret, F.X. (2014) Personalized drug combinations to overcome trastuzumab resistance in HER2-positive breast cancer. Biochim. Biophys. Acta, 1846(2): 353-365.
88. Escudier, B., Pluzanska, A., Koralewski, P., Ravaud, A., Bracarda, S., Szczylik, C., Chevreau, C., Filipek, M., Melichar, B., Bajetta, E., Gorbunova, V., Bay, J.O., Bodrogi, I., Jagiello-Gruszfeld, A. and Moore, N. (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet, 370(9605): 2103-2111.
89. Fu, W., Madan, E., Yee, M. and Zhang, H. (2012) Progress of molecular targeted therapies for prostate cancers. Biochim. Biophys. Acta Rev. Cancer, 1825(2): 140-152.
PMid:22146293 PMCid:PMC3307854
90. Chamberlain, M.C. (2011) Bevacizumab for the treatment of recurrent glioblastoma. Clin. Med. Insights Oncol., 5: 117-129.
PMid:21603247 PMCid:PMC3095028
91. Eswarakumar, V.P., Lax, I. and Schlessinger, J. (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev., 16(2): 139-149.
92. Du, Y., Hsu, J.L., Wang, Y.N. and Hung, M.C. (2014) Nuclear functions of receptor tyrosine kinases. In: Wheeler DL, Yarden Y, editors. Receptor Tyrosine Kinase: Structure, Functions and Role in Human Disease. 2015th ed. Springer, Heidelberg Dordrecht, New York, London, p77-109.
93. Greulich, H. and Pollock, P.M. (2011) Targeting mutant fibroblast growth factor receptors in cancer. Trends Mol. Med., 17(5): 283-292.
PMid:21367659 PMCid:PMC3809064
94. Gru, A.A. and Allred, D.C. (2012) FGFR1 amplification and the progression of non-invasive to invasive breast cancer. Breast Cancer Res., 14: 116.
PMid:23151501 PMCid:PMC4053127
95. Dutt, A., Ramos, A.H., Hammerman, P.S., Mermel, C., Cho, J., Sharifnia, T., Chande, A., Tanaka, K.E., Stransky, N., Greulich, H., Gray, N.S. and Meyerson, M. (2011) Inhibitor-sensitive fgfr1 amplification in human non-small cell lung cancer. PLoS One, 6(6): e20351.
96. Freier, K., Schwaenen, C., Sticht, C., Flechtenmacher, C., Mühling, J., Hofele, C., Radlwimmer, B., Lichter, P. and Joos, S. (2007) Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC). Oral Oncol., 43(1): 60-66.
97. McLendon, R., Friedman, A., Bigner, D., Van Meir, E.G., Brat, D.J.M., Mastrogianakis, G., Olson, J.J., Mikkelsen, T., Lehman, N., Aldape, K., Alfred Yung, W.K., Bogler, O., Vanden Berg, S., Berger, M., Prados, M., Muzny, D., Morgan, M., Scherer, S., Sabo, A., Nazareth, L., Lewis, L., Hall, O., Zhu, Y., Ren, Y., Alvi, O., Yao, J., Hawes, A., Jhangiani, S., Fowler, G., San Lucas, A., Kovar, C., Cree, A., Dinh, H., Santibanez, J., Joshi, V., Gonzalez-Garay, M.L., Miller, C.A., Milosavljevic, A., Donehower, L., Wheeler, D.A., Gibbs, R.A., Cibulskis, K., Sougnez, C., Fennell, T., Mahan, S., Wilkinson, J., Ziaugra, L., Onofrio, R., Bloom, T., Nicol, R., Ardlie, K., Baldwin, J., Gabriel, S., Lander, E.S., Ding, L., Fulton, R.S., McLellan, M.D., Wallis, J., Larson, D.E., Shi, X., Abbott, R., Fulton, L., Chen, K., Koboldt, D.C., Wendl, M.C., Meyer, R., Tang, Y., Lin, L., Osborne, J.R., Dunford-Shore, B.H., Miner, T.L., Delehaunty, K., Markovic, C., Swift, G., Courtney, W., Pohl, C., Abbott, S., Hawkins, A., Leong, S., Haipek, C., Schmidt, H., Wiechert, M., Vickery, T., Scott, S., Dooling, D.J., Chinwalla, A., Weinstock, G.M., Mardis, E.R., Wilson, R.K., Getz, G., Winckler, W., Verhaak, R.G.W., Lawrence, M.S., O'Kelly, M., Robinson, J., Alexe, G., Beroukhim, R., Carter, S., Chiang, D., Gould, J., Gupta, S., Korn, J., Mermel, C., Mesirov, J., Monti, S., Nguyen, H., Parkin, M., Reich, M., Stransky, N., Weir, B.A., Garraway, L., Golub, T., Meyerson, M., Chin, L., Protopopov, A., Zhang, J., Perna, I., Aronson, S., Sathiamoorthy, N., Ren, G., Yao, J., Wiedemeyer, W.R., Kim, H., Won Kong, S., Xiao, Y., Kohane, I.S., Seidman, J., Park, P.J., Kucherlapati, R., Laird, P.W., Cope, L., Herman, J.G., Weisenberger, D.J., Pan, F., Van Den Berg, D., Van Neste, L., Yi, J.M., Schuebel, K.E., Baylin, S.B., Absher, D.M., Li, J.Z., Southwick, A., Brady, S., Aggarwal, A., Chung, T., Sherlock, G., Brooks, J.D., Myers, R.M., Spellman, P.T., Purdom, E., Jakkula, L.R., Lapuk, A.V., Marr, H., Dorton, S., Gi Choi, Y., Han, J., Ray, A., Wang, V., Durinck, S., Robinson, M., Wang, N.J., Vranizan, K., Peng, V., Van Name, E., Fontenay, G.V., Ngai, J., Conboy, J.G., Parvin, B., Feiler, H.S., Speed, T.P., Gray, J.W., Brennan, C., Socci, N.D., Olshen, A., Taylor, B.S., Lash, A., Schultz, N., Reva, B., Antipin, Y., Stukalov, A., Gross, B., Cerami, E., Qing Wang, W., Qin, L.X., Seshan, V.E., Villafania, L., Cavatore, M., Borsu, L., Viale, A., Gerald, W., Sander, C., Ladanyi, M., Perou, C.M., Neil Hayes, D., Topal, M.D., Hoadley, K.A., Qi, Y., Balu, S., Shi, Y., Wu, J., Penny, R., Bittner, M., Shelton, T., Lenkiewicz, E., Morris, S., Beasley, D., Sanders, S., Kahn, A., Sfeir, R., Chen, J., Nassau, D., Feng, L., Hickey, E., Zhang, J., Weinstein, J.N., Barker, A., Gerhard, D.S., Vockley, J., Compton, C., Vaught, J., Fielding, P., Ferguson, M.L., Schaefer, C., Madhavan, S., Buetow, K.H., Collins, F., Good, P., Guyer, M., Ozenberger, B., Peterson, J. and Thomson, E. (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455(7216): 1061-1068.
PMid:18772890 PMCid:PMC2671642
98. Bai, A., Meetze, K., Vo, N.Y., Kollipara, S., Mazsa, E.K., Winston, W.M., Weiler, S., Poling, L.L., Chen, T., Ismail, N.S., Jiang, J., Lerner, L., Gyuris, J. and Weng, Z. (2010) GP369, an FGFR2-IIIb-specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. Cancer Res., 70(19): 7630-7639.
99. Katoh, Y. and Katoh, M. (2009) FGFR2-related pathogenesis and FGFR2-targeted therapeutics (review). Int. J. Mol. Med., 23(3): 307-311.
100. Dutt, A., Salvesen, H.B., Chen, T.H., Ramos, A.H., Onofrio, R.C., Hatton, C., Nicoletti, R., Winckler, W., Grewal, R., Hanna, M., Wyhs, N., Ziaugra, L., Richter, D.J., Trovik, J., Engelsen, I.B., Stefansson, I.M., Fennell, T., Cibulskis, K., Zody, M.C., Akslen, L.A., Gabriel, S., Wong, K.K., Sellers, W.R., Meyerson, M. and Greulich, H. (2008) Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl. Acad. Sci. U.S.A., 105(25): 8713-8717.
PMid:18552176 PMCid:PMC2438391
101. Cappellen, D., De Oliveira, C., Ricol, D., de Medina, S., Bourdin, J., Sastre-Garau, X., Chopin, D., Thiery, J.P. and Radvanyi, F. (1999) Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat. Genet., 23(1): 18-20.
102. Qing, J., Du, X., Chen, Y., Chan, P., Li, H., Wu, P., Marsters, S., Stawicki, S., Tien, J., Totpal, K., Ross, S., Stinson, S., Dornan, D., French, D., Wang, Q.R., Stephan, J.P., Wu, Y., Wiesmann, C. and Ashkenazi, A. (2009) Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J. Clin. Invest., 119(5): 1216-1229.
PMid:19381019 PMCid:PMC2673861
103. Tomlinson, D.C., Baldo, O., Hamden, P. and Knowles, M.A. (2007) FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J. Pathol., 213(1): 91-98.
PMid:17668422 PMCid:PMC2443273
104. Trudel, S., Stewart, A.K., Rom, E., Wei, E., Zhi, H.L., Kotzer, S., Chumakov, I., Singer, Y., Chang, H., Liang, S.B., Yayon, A., Li, Z.H., Kotzer, S., Chumakov, I. and Singer, Y. (2006) The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood, 107(10): 4039-4046.
105. Hernández, S., de Muga, S., Agell, L., Juanpere, N., Esgueva, R., Lorente, J. A., Mojal, S., Serrano, S. and Lloreta, J. (2009) FGFR3 mutations in prostate cancer: Association with low-grade tumors. Mod. Pathol., 22(6): 848-856.
106. Bange, J., Prechtl, D., Cheburkin, Y., Specht, K., Harbeck, N., Schmitt, M., Knyazeva, T., Müller, S., Gärtner, S., Sures, I., Wang, H., Imyanitov, E., Häring, H. U., Knayzev, P., Iacobelli, S., Höfler, H. and Ullrich, A. (2002) Cancer progression and tumor cell motility are associated with the FGFR4 Arg388 allele. Cancer Res., 62(3): 840-847.
107. Roidl, A., Berger, H. J., Kumar, S., Bange, J., Knyazev, P. and Ullrich, A. (2009) Resistance to chemotherapy is associated with fibroblast growth factor receptor 4 up-regulation. Clin. Cancer Res., 15(6): 2058-2066.
108. Roidl, A., Foo, P., Wong, W., Mann, C., Bechtold, S., Berger, H.J., Streit, S., Ruhe, J.E., Hart, S., Ullrich, A. and Ho, H.K. (2010) The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene, 29(10): 1543-1552.
109. Mohammadi, M., Froum, S., Hamby, J.M., Schroeder, M.C., Panek, R.L., Lu, G.H., Eliseenkova, A.V, Green, D., Schlessinger, J. and Hubbard, S.R. (1998) Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J., 17(20): 5896-5904.
PMid:9774334 PMCid:PMC1170917
110. Koziczak, M., Holbro, T. and Hynes, N.E. (2004) Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene, 23(20): 3501-3508.
111. Fischer, H., Taylor, N., Allerstorfer, S., Grusch, M., Sonvilla, G., Holzmann, K., Setinek, U., Elbling, L., Cantonati, H., Grasl-Kraupp, B., Gauglhofer, C., Marian, B., Micksche, M. and Berger, W. (2008) Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: Therapeutic implications and synergism with epidermal growth factor receptor inhibition. Mol. Cancer Ther., 7(10): 3408-3419.
PMid:18852144 PMCid:PMC2879863
112. Lamont, F.R., Tomlinson, D.C., Cooper, P.A., Shnyder, S.D., Chester, J.D. and Knowles, M.A. (2011) Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo. Br. J. Cancer, 104(1): 75-82.
PMid:21119661 PMCid:PMC3039817
113. Wedge, S.R., Kendrew, J., Hennequin, L.F., Valentine, P.J., Barry, S.T., Brave, S.R., Smith, N.R., James, N.H., Dukes, M., Curwen, J.O., Chester, R., Jackson, J.A., Boffey, S.J., Kilburn, L.L., Barnett, S., Richmond, G.H.P., Wadsworth, P.F., Walker, M., Bigley, A.L., Taylor, S.T., Cooper, L., Beck, S., Jürgensmeier, J.M. and Ogilvie, D.J. (2005) AZD2171: A highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res., 65(10): 4389-4400.
114. Nakamura, K., Yashiro, M., Matsuoka, T., Tendo, M., Shimizu, T., Miwa, A. and Hirakawa, K. (2006) A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for scirrhous gastric cancer. Gastroenterology, 131(5): 1530-1541.
115. Yashiro, M., Shinto, O., Nakamura, K., Tendo, M., Matsuoka, T., Matsuzaki, T., Kaizaki, R., Miwa, A. and Hirakawa, K. (2010) Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma. Int. J. Cancer, 126(4): 1004-1016.
116. Dienstmann, R., Rodon, J., Prat, A., Perez-Garcia, J., Adamo, B., Felip, E., Cortes, J., Iafrate, A.J., Nuciforo, P. and Tabernero, J. (2014) Genomic aberrations in the FGFR pathway: Opportunities for targeted therapies in solid tumors. Ann. Oncol., 25(3): 552-563.
PMid:24265351 PMCid:PMC4433501
117. Harding, T.C., Long, L., Palencia, S., Zhang, H., Sadra, A., Hestir, K., Patil, N., Levin, A., Hsu, A. W., Charych, D., Brennan, T., Zanghi, J., Halenbeck, R., Marshall, S.A, Qin, M., Doberstein, S.K., Hollenbaugh, D., Kavanaugh, W.M., Williams, L.T. and Baker, K.P. (2013) Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer. Sci. Trans. Med., 5(178): 178ra39.
118. Baker, K.P. and Los, G. (2013) Targeting fibroblast growth factors in cancer: The key is what not to block. Oncotarget, 4(7): 950-951.
119. Mansoor, Q., Fayyaz, S., Farooqi, A.A., Bhatti, S. and Ismail, M. (2013) Re-evaluating the FGFR4 (G388R) germline mutation in different cancers in Pakistani population. J. Exp. Ther. Oncol., 10(3): 215-217.
120. Olmos, D., Basu, B. and de Bono, J.S. (2010) Targeting insulin-like growth factor signaling: Rational combination strategies. Mol. Cancer Ther., 9(9): 2447-2449.
121. Ryan, P.D. and Goss, P.E. (2008) The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer. Oncologist, 13(1): 16-24.
122. Reinmuth, N., Fan, F., Liu, W., Parikh, A.A., Stoeltzing, O., Jung, Y.D., Bucana, C.D., Radinsky, R., Gallick, G.E. and Ellis, L.M. (2002) Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. Lab. Invest., 82(10): 1377-1389.
123. Yee, D. (2012) Insulin-like growth factor receptor inhibitors: Baby or the bathwater? J. Natl. Cancer Inst., 104(13): 975-981.
PMid:22761272 PMCid:PMC3634550
124. Nakamura, T. and Mizuno, S. (2010) The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci., 86(6): 588-610.
125. Edakuni, G., Sasatomi, E., Satoh, T., Tokunaga, O. and Miyazaki, K. (2001) Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma. Pathol. Int., 51(3): 172-178.
126. Maulik, G., Kijima, T., Ma, P.C., Ghosh, S.K., Lin, J., Shapiro, G.I., Schaefer, E., Tibaldi, E., Johnson, B.E. and Salgia, R. (2002) Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin. Cancer Res., 8(2): 620-627.
127. Inoue, T., Kataoka, H., Goto, K., Nagaike, K., Igami, K., Naka, D., Kitamura, N. and Miyazawa, K. (2004) Activation of c-Met (hepatocyte growth factor receptor) in human gastric cancer tissue. Cancer Sci., 95(10): 803-808.
128. Liu, Y., Li, Q. and Zhu, L. (2012) Expression of the hepatocyte growth factor and c-Met in colon cancer: Correlation with clinicopathological features and overall survival. Tumori, 98(1): 105-112.
129. Harshman, L.C. and Choueiri, T.K. (2013) Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J., 19(4): 316-323.
130. Blumenschein, G.R., Mills, G.B. and Gonzalez-Angulo, A.M. (2012) Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J. Clin. Oncol., 30(26): 3287-3296.
PMid:22869872 PMCid:PMC3434988
131. Green, J.L., Kuntz, S.G. and Sternberg, P.W. (2008) Ror receptor tyrosine kinases: Orphans no more. Trends Cell Biol., 18(11): 536-544.
PMid:18848778 PMCid:PMC4672995
132. Matsuda, T., Nomi, M., Ikeya, M., Kani, S., Oishi, I., Terashima, T., Takada, S. and Minami, Y. (2001) Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development. Mech. Dev., 105(1-2): 153-156.
133. Al-Shawi, R., Ashton, S.V., Underwood, C. and Simons, J.P. (2001) Expression of the Ror1 and Ror2 receptor tyrosine kinase genes during mouse development. Dev. Genes Evol., 211(4): 161-171.
134. Uhrmacher, S., Schmidt, C., Erdfelder, F., Poll-Wolbeck, S.J., Gehrke, I., Hallek, M. and Kreuzer, K.A. (2011) Use of the receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a diagnostic tool in chronic lymphocytic leukemia (CLL). Leuk. Res., 35(10): 1360-1366.
135. Daneshmanesh, A.H., Porwit, A., Hojjat-Farsangi, M., Jeddi-Tehrani, M., Tamm, K.P., Grandér, D., Lehmann, S., Norin, S., Shokri, F., Rabbani, H., Mellstedt, H. and Österborg, A. (2012) Orphan receptor tyrosine kinases ROR1 and ROR2 in hematological malignancies. Leuk. Lymphoma, 54(4): 1-8.
136. Zhang, S., Cui, B., Lai, H., Liu, G., Ghia, E.M., Widhopf, G.F., Zhang, Z., Wu, C.C.N., Chen, L., Wu, R., Schwab, R., Carson, D.A. and Kipps, T.J. (2014) Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy. Proc. Natl. Acad. Sci., 111(48): 17266-17271.
PMid:25411317 PMCid:PMC4260559
137. Hojjat-Farsangi, M., Ghaemimanesh, F., Daneshmanesh, A.H., Bayat, A.A., Mahmoudian, J., Jeddi-Tehrani, M., Rabbani, H. and Mellstedt, H. (2013) Inhibition of the receptor tyrosine kinase ROR1 by anti-ROR1 monoclonal antibodies and siRNA induced apoptosis of melanoma cells. PLoS One, 8(4): e61167.
138. Marchetti, C., Gasparri, M.L., Ruscito, I., Palaia, I., Perniola, G., Carrone, A., Farooqi, A.A., Pecorini, F., Muzii, L. and Panici, P.B. (2015) Advances in anti-angiogenic agents for ovarian cancer treatment: The role of trebananib (AMG 386). Critc. Rev. Oncol. Hematol., 94(3): 302-310.
139. Farooqi, A.A., Waseem, S., Riaz, A.M., Dilawar, B.A., Mukhtar, S., Minhaj, S., Waseem, M.S., Daniel, S., Malik, B.A., Nawaz, A. and Bhatti, S. (2011) PDGF: The nuts and bolts of signalling toolbox. Tumor Biol., 32(6): 1057-1070.
140. Farooqi, A.A. and Siddik, Z.H. (2015) Platelet-derived growth factor (PDGF) signalling in cancer: Rapidly emerging signalling landscape. Cell Biochem. Funct., 33(5): 257-265.