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Journal of Thyroid Research
Volume 2011 (2011), Article ID 678357, 10 pages
http://dx.doi.org/10.4061/2011/678357
Review Article

How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer

1Cancer Biology Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal
2Molecular Pathology Service, Portuguese Institute of Oncology of Coimbra FG, EPE, Avenida Bissaya Barreto, 98, 3000-075 Coimbra, Portugal
3Department of Pathology, Faculty of Medicine of Porto University, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
4Endocrinology Service, Portuguese Institute of Oncology of Coimbra FG, EPE, Avenida Bissaya Barreto, 98, 3000-075 Coimbra, Portugal
5Abel Salazar Biomedical Sciences Institute (ICBAS), Lg. Prof. Abel Salazar, 4099-003 Porto, Portugal
6Department of Pathology, Hospital São João, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

Received 11 February 2011; Accepted 10 April 2011

Academic Editor: Maria João M. Bugalho

Copyright © 2011 Hugo Prazeres et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Takahashi and G. M. Cooper, “ret Transforming gene encodes a fusion protein homologous to tyrosine kinases,” Molecular and Cellular Biology, vol. 7, no. 4, pp. 1378–1385, 1987. View at Google Scholar · View at Scopus
  2. M. S. Airaksinen, A. Titievsky, and M. Saarma, “GDNF family neurotrophic factor signaling: four masters, one servant,” Molecular and Cellular Neurosciences, vol. 13, no. 5, pp. 313–325, 1999. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Fukuda, K. Kiuchi, and M. Takahashi, “Novel mechanism of regulation of Rac activity and lamellipodia formation by RET tyrosine kinase,” Journal of Biological Chemistry, vol. 277, no. 21, pp. 19114–19121, 2002. View at Publisher · View at Google Scholar · View at Scopus
  4. A. Pandey, X. Liu, J. E. Dixon, P. P. Di Fiore, and V. M. Dixit, “Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7,” Journal of Biological Chemistry, vol. 271, no. 18, pp. 10607–10610, 1996. View at Publisher · View at Google Scholar · View at Scopus
  5. G. R. Panta, F. Nwariaku, and L. T. Kim, “RET signals through focal adhesion kinase in medullary thyroid cancer cells,” Surgery, vol. 136, no. 6, pp. 1212–1217, 2004. View at Publisher · View at Google Scholar · View at Scopus
  6. J. W. B. De Groot, T. P. Links, J. T. M. Plukker, C. J. M. Lips, and R. M. W. Hofstra, “RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors,” Endocrine Reviews, vol. 27, no. 5, pp. 535–560, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. H. Murakami, T. Iwashita, N. Asai et al., “Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by Ret with the MEN 2B mutation,” Biochemical and Biophysical Research Communications, vol. 262, no. 1, pp. 68–75, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Segouffin-Cariou and M. Billaud, “Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway,” Journal of Biological Chemistry, vol. 275, no. 5, pp. 3568–3576, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. M. Chiariello, R. Visconti, F. Carlomagno et al., “Signalling of the Ret receptor tyrosine kinase through the c-Jun NH-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret,” Oncogene, vol. 16, no. 19, pp. 2435–2445, 1998. View at Google Scholar · View at Scopus
  10. E. Arighi, M. G. Borrello, and H. Sariola, “RET tyrosine kinase signaling in development and cancer,” Cytokine and Growth Factor Reviews, vol. 16, no. 4-5, pp. 441–467, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. T. S. Gujral, W. Van Veelen, D. S. Richardson et al., “A novel RET kinase-β-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma,” Cancer Research, vol. 68, no. 5, pp. 1338–1346, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Takahashi, J. Ritz, and G. M. Cooper, “Activation of a novel human transforming gene, ret, by DNA rearrangement,” Cell, vol. 42, no. 2, pp. 581–588, 1985. View at Google Scholar · View at Scopus
  13. D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000. View at Google Scholar · View at Scopus
  14. T. Watanabe, M. Ichihara, M. Hashimoto et al., “Characterization of gene expression induced by RET with MEN2A or MEN2B mutation,” American Journal of Pathology, vol. 161, no. 1, pp. 249–256, 2002. View at Google Scholar · View at Scopus
  15. J. J. Schuringa, K. Wojtachnio, W. Hagens et al., “MEN2A-RET-induced cellular transformation by activation of STAT3,” Oncogene, vol. 20, no. 38, pp. 5350–5358, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. N. Asai, T. Fukuda, Z. Wu et al., “Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells,” Development, vol. 133, no. 22, pp. 4507–4516, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. G. W. McLean, N. O. Carragher, E. Avizienyte, J. Evans, V. G. Brunton, and M. C. Frame, “The role of focal-adhesion kinase in cancer—a new therapeutic opportunity,” Nature Reviews Cancer, vol. 5, no. 7, pp. 505–515, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. F. Colotta, P. Allavena, A. Sica, C. Garlanda, and A. Mantovani, “Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability,” Carcinogenesis, vol. 30, no. 7, pp. 1073–1081, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. M. G. Borrello, L. Alberti, A. Fischer et al., “Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 41, pp. 14825–14830, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. N. Iwahashi, H. Murakami, Y. Nimura, and M. Takahashi, “Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signaling pathways,” Biochemical and Biophysical Research Communications, vol. 294, no. 3, pp. 642–649, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Shinohara and J. L. Rothstein, “Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells,” Oncogene, vol. 23, no. 45, pp. 7571–7579, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. V. Guarino, M. D. Castellone, E. Avilla, and R. M. Melillo, “Thyroid cancer and inflammation,” Molecular and Cellular Endocrinology, vol. 321, no. 1, pp. 94–102, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. E. Puxeddu, J. A. Knauf, M. A. Sartor et al., “RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response,” Endocrine-Related Cancer, vol. 12, no. 2, pp. 319–334, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Muzza, D. Degl'Innocenti, C. Colombo et al., “The tight relationship between papillary thyroid cancer, autoimmunity and inflammation: clinical and molecular studies,” Clinical Endocrinology, vol. 72, no. 5, pp. 702–708, 2010. View at Publisher · View at Google Scholar
  25. M. G. Borrello, D. Degl'Innocenti, and M. A. Pierotti, “Inflammation and cancer: the oncogene-driven connection,” Cancer Letters, vol. 267, no. 2, pp. 262–270, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. L. M. Mulligan, J. B. J. Kwok, C. S. Healey et al., “Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A,” Nature, vol. 363, no. 6428, pp. 458–460, 1993. View at Publisher · View at Google Scholar · View at Scopus
  27. H. Donis-Keller, S. Dou, D. Chi et al., “Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC,” Human Molecular Genetics, vol. 2, no. 7, pp. 851–856, 1993. View at Google Scholar · View at Scopus
  28. C. Eng, D. Clayton, I. Schuffenecker et al., “The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis,” Journal of the American Medical Association, vol. 276, no. 19, pp. 1575–1579, 1996. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Santoro, F. Carlomagno, A. Romano et al., “Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B,” Science, vol. 267, no. 5196, pp. 381–383, 1995. View at Google Scholar · View at Scopus
  30. M. D. Castellone, A. Verrienti, D. Magendra Rao et al., “A novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization,” Clinical Endocrinology, vol. 73, no. 4, pp. 529–534, 2010. View at Publisher · View at Google Scholar
  31. F. Lesueur, A. Cebrian, A. Cranston et al., “Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 6, pp. 3454–3457, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. P. Pigny, C. Bauters, J. L. Wemeau et al., “A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 5, pp. 1700–1704, 1999. View at Google Scholar · View at Scopus
  33. A. N. Cranston, C. Carniti, K. Oakhill et al., “RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B,” Cancer Research, vol. 66, no. 20, pp. 10179–10187, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. P. Soares, V. Trovisco, A. S. Rocha et al., “BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC,” Oncogene, vol. 22, no. 29, pp. 4578–4580, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. R. M. W. Hofstra, R. M. Landsvater, I. Ceccherini et al., “A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma,” Nature, vol. 367, no. 6461, pp. 375–376, 1994. View at Publisher · View at Google Scholar · View at Scopus
  36. O. Gimm, D. J. Marsh, S. D. Andrew et al., “Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 11, pp. 3902–3904, 1997. View at Google Scholar · View at Scopus
  37. A. Miyauchi, H. Futami, N. Hai et al., “Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation,” Japanese Journal of Cancer Research, vol. 90, no. 1, pp. 1–5, 1999. View at Google Scholar · View at Scopus
  38. P. J. Morrison and N. C. Nevin, “Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome),” Journal of Medical Genetics, vol. 33, no. 9, pp. 779–782, 1996. View at Google Scholar · View at Scopus
  39. S. Bethanis, G. Koutsodontis, T. Palouka et al., “A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A,” Hormones, vol. 6, no. 2, pp. 152–156, 2007. View at Google Scholar · View at Scopus
  40. I. Berndt, M. Reuter, B. Saller et al., “A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 3, pp. 770–774, 1998. View at Publisher · View at Google Scholar · View at Scopus
  41. G. Pinna, G. Orgiana, A. Riola et al., “RET proto-oncogene in Sardinia: V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype,” Thyroid, vol. 17, no. 2, pp. 101–104, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. C. Jimenez, M. A. Habra, S. C. E. Huang et al., “Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 8, pp. 4142–4145, 2004. View at Publisher · View at Google Scholar · View at Scopus
  43. F. Raue and K. Frank-Raue, “Multiple endocrine neoplasia type 2: 2007 update,” Hormone Research, vol. 68, supplement 5, pp. 101–104, 2007. View at Google Scholar · View at Scopus
  44. R. T. Kloos, C. Eng, D. B. Evans et al., “Medullary thyroid cancer: management guidelines of the American Thyroid Association,” Thyroid, vol. 19, no. 6, pp. 565–612, 2009. View at Google Scholar · View at Scopus
  45. S. Dvorakova, E. Vaclavikova, V. Sykorova et al., “Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas,” Molecular and Cellular Endocrinology, vol. 284, no. 1-2, pp. 21–27, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. M. M. Moura, B. M. Cavaco, A. E. Pinto et al., “Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas,” British Journal of Cancer, vol. 100, no. 11, pp. 1777–1783, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. X. Liu, Q. C. Vega, R. A. Decker, A. Pandey, C. A. Worby, and J. E. Dixon, “Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities,” Journal of Biological Chemistry, vol. 271, no. 10, pp. 5309–5312, 1996. View at Publisher · View at Google Scholar · View at Scopus
  48. D. Salvatore, R. M. Melillo, C. Monaco et al., “Increased in vivo phosphorylation of ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B,” Cancer Research, vol. 61, no. 4, pp. 1426–1431, 2001. View at Google Scholar · View at Scopus
  49. I. P. Menacho, R. Koster, A. M. Van Der Sloot et al., “RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor,” Cancer Research, vol. 65, no. 5, pp. 1729–1737, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. F. Carlomagno, D. Vitagliano, T. Guida et al., “The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes,” Cancer Research, vol. 62, no. 4, pp. 1077–1082, 2002. View at Google Scholar · View at Scopus
  51. F. Carlomagno, D. Vitagliano, T. Guida et al., “ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases,” Cancer Research, vol. 62, no. 24, pp. 7284–7290, 2002. View at Google Scholar · View at Scopus
  52. C. Lanzi, G. Cassinelli, T. Pensa et al., “Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative,” International Journal of Cancer, vol. 85, no. 3, pp. 384–390, 2000. View at Google Scholar · View at Scopus
  53. D. W. Kim, Y. S. Jo, H. S. Jung et al., “An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 10, pp. 4070–4076, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. S. J. Dawson, N. M. Conus, G. C. Toner et al., “Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma,” Anti-Cancer Drugs, vol. 19, no. 5, pp. 547–552, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Croyle, N. Akeno, J. A. Knauf et al., “RET/PTC-induced cell growth is mediated in part by epidermal growth factor receptor (EGFR) activation: evidence for molecular and functional interactions between RET and EGFR,” Cancer Research, vol. 68, no. 11, pp. 4183–4191, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. N. A. Pennell, G. H. Daniels, R. I. Haddad et al., “A phase II study of gefitinib in patients with advanced thyroid cancer,” Thyroid, vol. 18, no. 3, pp. 317–323, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. F. Carlomagno, S. Anaganti, T. Guida et al., “BAY 43-9006 inhibition of oncogenic RET mutants,” Journal of the National Cancer Institute, vol. 98, no. 5, pp. 326–334, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. V. Gupta-Abramson, A. B. Troxel, A. Nellore et al., “Phase II trial of sorafenib in advanced thyroid cancer,” Journal of Clinical Oncology, vol. 26, no. 29, pp. 4714–4719, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. S. I. Sherman, L. J. Wirth, J. P. Droz et al., “Motesanib diphosphate in progressive differentiated thyroid cancer,” New England Journal of Medicine, vol. 359, no. 1, pp. 31–42, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. M. J. Schlumberger, R. Elisei, L. Bastholt et al., “Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer,” Journal of Clinical Oncology, vol. 27, no. 23, pp. 3794–3801, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. E. E. W. Cohen, L. S. Rosen, E. E. Vokes et al., “Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study,” Journal of Clinical Oncology, vol. 26, no. 29, pp. 4708–4713, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. J. P. Eder, L. Appleman, E. Heath et al., “A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs),” Journal of Clinical Oncology, vol. 24, no. 18S, p. 3041, 2006, ASCO Annual Meeting Proceedings Part I. View at Google Scholar
  63. P. LoRusso, L. Appleman, A. X. Zhu et al., “Pharmacodynamics of XL880, a novel spectrum selective kinase inhibitor (SSKI) administered orally in patients with advanced solid tumors (AST),” in Proceedings of the 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Prague, Czech Republic, November 2006, Abstract 404.
  64. R. W. Ross, M. Stein, J. Sarantopoulos et al., “A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC),” Journal of Clinical Oncology, vol. 25, no. 18S, p. 15601, 2007, ASCO Annual Meeting Proceedings. View at Google Scholar
  65. R. Salgia, D. S. Hong, L. H. Camacho et al., “A phase I dose-escalation study of the safety and pharmacokinetics (PK) of XL184, a VEGFR and MET kinase inhibitor, administered orally to patients (pts) with advanced malignancies,” Journal of Clinical Oncology, vol. 25, no. 18S, p. 14031, 2007, ASCO Annual Meeting Proceedings. View at Google Scholar
  66. C. J. Strock, J. I. Park, M. Rosen et al., “CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth,” Cancer Research, vol. 63, no. 17, pp. 5559–5563, 2003. View at Google Scholar · View at Scopus
  67. M. S. Cohen, H. B. Hussain, and J. F. Moley, “Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors,” Surgery, vol. 132, no. 6, pp. 960–967, 2002. View at Publisher · View at Google Scholar · View at Scopus
  68. M. A. Skinner, J. A. Moley, W. G. Dilley, K. Owzar, M. K. DeBenedetti, and S. A. Wells, “Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A,” New England Journal of Medicine, vol. 353, no. 11, pp. 1105–1113, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. J. F. Lyons, S. Wilhelm, B. Hibner, and G. Bollag, “Discovery of a novel Raf kinase inhibitor,” Endocrine-Related Cancer, vol. 8, no. 3, pp. 219–225, 2001. View at Publisher · View at Google Scholar · View at Scopus
  70. Y. C. Henderson, S. H. Ann, Y. Kang, and G. L. Clayman, “Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement,” Clinical Cancer Research, vol. 14, no. 15, pp. 4908–4914, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. C. Lanzi, G. Cassinelli, G. Cuccuru et al., “Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1,” Cellular and Molecular Life Sciences, vol. 60, no. 7, pp. 1449–1459, 2003. View at Publisher · View at Google Scholar · View at Scopus
  72. D. B. Mendel, A. Douglas Laird, X. Xin et al., “In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship,” Clinical Cancer Research, vol. 9, no. 1, pp. 327–337, 2003. View at Google Scholar · View at Scopus
  73. T. J. Abrams, L. B. Lee, L. J. Murray, N. K. Pryer, and J. M. Cherrington, “SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer,” Molecular Cancer Therapeutics, vol. 2, no. 5, pp. 471–478, 2003. View at Google Scholar
  74. C. J. Strock, J. I. Park, D. M. Rosen et al., “Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 1, pp. 79–84, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. S. D. Undevia, N. J. Vogelzang, A. M. Mauer, L. Janisch, S. Mani, and M. J. Ratain, “Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors,” Investigational New Drugs, vol. 22, no. 4, pp. 449–458, 2004. View at Publisher · View at Google Scholar · View at Scopus
  76. T. K. Choueiri, “Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors,” Current Opinion in Investigational Drugs, vol. 9, no. 6, pp. 658–671, 2008. View at Google Scholar · View at Scopus
  77. A. Polverino, A. Coxon, C. Starnes et al., “AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts,” Cancer Research, vol. 66, no. 17, pp. 8715–8721, 2006. View at Publisher · View at Google Scholar · View at Scopus
  78. F. Carlomagno, T. Guida, S. Anaganti et al., “Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors,” Oncogene, vol. 23, no. 36, pp. 6056–6063, 2004. View at Publisher · View at Google Scholar · View at Scopus
  79. P. P. Knowles, J. Murray-Rust, S. Kjær et al., “Structure and chemical inhibition of the RET tyrosine kinase domain,” Journal of Biological Chemistry, vol. 281, no. 44, pp. 33577–33587, 2006. View at Publisher · View at Google Scholar · View at Scopus
  80. I. Plaza-Menacho, L. Mologni, E. Sala et al., “Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting,” Journal of Biological Chemistry, vol. 282, no. 40, pp. 29230–29240, 2007. View at Publisher · View at Google Scholar · View at Scopus
  81. D. G. Pfister and J. A. Fagin, “Refractory thyroid cancer: a paradigm shift in treatment is not far off,” Journal of Clinical Oncology, vol. 26, no. 29, pp. 4701–4704, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. P. P. Joshi, M. V. Kulkarni, B. K. Yu et al., “Simultaneous downregulation of CDK inhibitors p18 and p27 is required for MEN2A-RET-mediated mitogenesis,” Oncogene, vol. 26, no. 4, pp. 554–570, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. W. Van Veelen, C. J. R. Van Gasteren, D. S. Acton et al., “Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development,” Cancer Research, vol. 68, no. 5, pp. 1329–1337, 2008. View at Publisher · View at Google Scholar · View at Scopus