Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy

Abstract

Growing evidence supports the concept of oncogene dependence for cancer development; inhibition of the initiating oncogene can result in revertion of the neoplastic phenotype. The outstanding role of the RET proto-oncogene in the development of medullary thyroid carcinoma (MTC) is well established. With the emerging knowledge concerning the signal transduction pathways leading to subsequent neoplastic transformation, oncogenic activated RET becomes a highly attractive target for selective cancer therapy. A variety of novel approaches that target RET directly or indirectly have recently emerged and an increasing number are currently being assessed in clinical trials. In view of these findings, it becomes strikingly obvious that inhibition of RET oncogene function can be a viable option for the treatment of MTC. We summarize the current evidence for RET involvement in the etiology of MTC, and the therapeutic targeting of this process in preclinical and clinical studies.

Key Points

  • Mutations in the RET proto-oncogene are responsible for the development of medullary thyroid carcinoma, which occurs sporadically or as part of the inherited cancer syndrome, multiple endocrine neoplasia type 2

  • RET is a tyrosine kinase receptor implicated in developmental processes and neural survival

  • Mutations activate RET in a constitutive fashion which, in turn, results in aberrant stimulation of downstream signal transduction pathways that mediate cell proliferation and survival

  • Several strategies have been developed to block hyperactive RET in preclinical models of medullary thyroid carcinoma, and these models show that RET inhibition results in a loss of neoplastic phenotypes

  • Some approaches to target RET have already entered investigation in clinical trials

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure of the receptor tyrosine kinase RET.
Figure 2: Mechanisms of RET activation.
Figure 3: RET signaling components.
Figure 4: Principles of RET inhibition.

Similar content being viewed by others

References

  1. Weinstein IB (2002) Cancer: addiction to oncogenes–the Achilles heal of cancer. Science 297: 63–64

    CAS  PubMed  Google Scholar 

  2. Fischer OM et al. (2003) Beyond Herceptin and Gleevec. Curr Opin Chem Biol 7: 490–495

    CAS  PubMed  Google Scholar 

  3. Ross JS et al. (2004) Targeted therapies for cancer 2004. Am J Clin Pathol 122: 598–609

    CAS  PubMed  Google Scholar 

  4. Vitale G et al. (2001) Current approaches and perspectives in the therapy of medullary thyroid carcinoma. Cancer 91: 1797–1808

    CAS  PubMed  Google Scholar 

  5. Quayle FJ and Moley JF (2005) Medullary thyroid carcinoma: including MEN 2 A and MEN 2B syndromes. J Surg Oncol 89: 122–129

    PubMed  Google Scholar 

  6. Pützer BM and Drosten M (2004) The RET proto-oncogene: a potential target for molecular cancer therapy. Trends Mol Med 10: 351–357

    PubMed  Google Scholar 

  7. Arighi E et al. (2005) RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16: 441–467

    CAS  PubMed  Google Scholar 

  8. Airaksinen MF and Saarma M (2002) The GDNF family: signaling, biological functions and therapeutic value. Nat Rev Neurosci 3: 383–394

    CAS  PubMed  Google Scholar 

  9. Coulpier M et al. (2002) Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survival. J Biol Chem 277: 1991–1999

    CAS  PubMed  Google Scholar 

  10. Baloh RH et al. (2000) The GDNF family ligands and receptors–implications for neural development. Curr Opin Neurobiol 10: 103–110

    CAS  PubMed  Google Scholar 

  11. Schuchardt A et al. (1994) Defects in the kidney and enteric nervous system in mice lacking the tyrosine kinase receptor Ret. Nature 367: 380–383

    CAS  PubMed  Google Scholar 

  12. Sanchez MP et al. (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382: 70–73

    CAS  PubMed  Google Scholar 

  13. Cacalano G et al. (1998) GFRα1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21: 53–62

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Jain S et al. (2004) Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis. Development 131: 5503–5513

    CAS  PubMed  Google Scholar 

  15. Takahashi M (2001) The GDNF/RET signaling pathways and human diseases. Cytokine Growth Factor Rev 12: 361–373

    CAS  PubMed  Google Scholar 

  16. Manie S et al. (2001) The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet 17: 580–589

    CAS  PubMed  Google Scholar 

  17. Jijiwa M et al. (2004) A targeted mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia. Mol Cell Biol 24: 8026–8036

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wong A et al. (2005) Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform. Mol Cell Biol 25: 9661–9673

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Schuringa JJ et al. (2001) MEN2A-RET-induced cellular transformation by activation of STAT3. Oncogene 20: 5350–5358

    CAS  PubMed  Google Scholar 

  20. Schuetz G et al. (2004) The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells. J Cell Biol 167: 945–952

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Besset V et al. (2000) Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase. J Biol Chem 275: 39159–39166

    CAS  PubMed  Google Scholar 

  22. Hayashi H et al. (2000) Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Oncogene 19: 4469–4475

    CAS  PubMed  Google Scholar 

  23. Coleman ML et al. (2004) RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Cell Biol 5: 355–366

    CAS  PubMed  Google Scholar 

  24. Vivanco I and Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2: 498–501

    Google Scholar 

  25. Degl'Innocenti D et al. (2004) Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching. Oncogene 23: 7297–7309

    CAS  PubMed  Google Scholar 

  26. Hayashi Y et al. (2001) Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation. Biochem Biophys Res Commun 281: 682–689

    CAS  PubMed  Google Scholar 

  27. Borrello MG et al. (1996) The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phosphlipase Cγ. Mol Cell Biol 16: 2151–2163

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gimm O (2001) Thyroid cancer. Cancer Lett 163: 143–156

    CAS  PubMed  Google Scholar 

  29. Hundahl SA et al. (1998) A National Cancer Database report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995. Cancer 83: 2638–2648

    CAS  PubMed  Google Scholar 

  30. Leboulleux S et al. (2004) Medullary thyroid carcinoma. Clin Endocrinol 61: 299–310

    Google Scholar 

  31. Cohen MS and Moley JF (2003) Surgical treatment of medullary thyroid carcinoma. J Intern Med 253: 616–626

    CAS  PubMed  Google Scholar 

  32. Brandi ML et al. (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86: 5658–5671

    CAS  PubMed  Google Scholar 

  33. Mulligan LM et al. (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363: 458–460

    CAS  PubMed  Google Scholar 

  34. Hofstra RM et al. (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2 B and sporadic medullary thyroid carcinoma. Nature 367: 375–376

    CAS  PubMed  Google Scholar 

  35. Eng C et al. (1996) The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. JAMA 276: 1575–1579

    CAS  PubMed  Google Scholar 

  36. Asai N et al. (1995) Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia type 2 mutations. Mol Cell Biol 15: 1613–1619

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Santoro M et al. (1995) Activation of RET as a dominant-transforming gene by germline mutations of MEN2 A and MEN2B. Science 267: 381–383

    CAS  PubMed  Google Scholar 

  38. Bocciardi R et al. (1997) The multiple endocrine neoplasia type 2B mutation switches the specificity of the Ret tyrosine kinase towards cellular substrates that are susceptible to interact with Crk and Nck. Oncogene 15: 2257–2265

    CAS  PubMed  Google Scholar 

  39. Salvatore D et al. (2001) Increased in vivo phosphorylation of tyrosine 1062 is a potential pathogenic mechanism of multiple endocrine neoplasia type 2B. Cancer Res 61: 1426–1431

    CAS  PubMed  Google Scholar 

  40. Carlomagno F et al. (1995) Point mutation of the RET proto-oncogene in the TT human medullary thyroid carcinoma cell line. Biochem Biophys Res Commun 207: 1022–1028

    CAS  PubMed  Google Scholar 

  41. Drosten M et al. (2004) Role of MEN2A-derived RET in maintenance and proliferation of medullary thyroid carcinoma. J Natl Cancer Inst 96: 1231–1239

    CAS  PubMed  Google Scholar 

  42. Wang DG et al. (1998) Bcl-2 and c-myc, but not bax and p53, are expressed during human medullary thyroid carcinoma tumorigenesis. Am J Pathol 152: 1407–1413

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Reynolds L et al. (2001) C-cell and thyroid epithelial tumors and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET. Oncogene 20: 3986–3994

    CAS  PubMed  Google Scholar 

  44. Cerchia L et al. (2003) The soluble ectodomain of RETC634Y inhibits both the wild-type and the constitutively activated RET. Biochem J 372: 897–903

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Doggrell SA (2005) Pegaptanib: the first antiangiogenic agent approved for neovascular macular degeneration. Exp Opin Pharmacother 6: 1421–1423

    CAS  Google Scholar 

  46. Cerchia L et al. (2005) Neutralizing aptamers from whole-cell SELEX inhibit the RET receptor tyrosine kinase. PloS Biol 3: e123

    PubMed  PubMed Central  Google Scholar 

  47. Cosma MP et al. (1998) Mutations in the extracellular domain cause RET loss of function by a dominant negative mechanism. Mol Cell Biol 18: 3321–3329

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Drosten M et al. (2002) A new therapeutic approach in medullary thyroid cancer treatment: inhibition of oncogenic RET signaling by adenoviral vector-mediated expression of a dominant-negative RET mutant. Surgery 132: 991–997

    PubMed  Google Scholar 

  49. Drosten M et al. (2003) Antitumor capacity of a dominant-negative RET proto-oncogene mutant in a medullary thyroid carcinoma model. Hum Gene Ther 14: 971–982

    CAS  PubMed  Google Scholar 

  50. Böckmann M et al. (2004) Discovery of targeting peptides for selective therapy of medullary thyroid carcinoma. J Gene Med 7: 179–188

    Google Scholar 

  51. Böckmann M et al. (2005) Novel SRESPHP peptide mediates specific binding to primary medullary thyroid carcinoma after systemic injection. Hum Gene Ther 16: 1267–1275

    PubMed  Google Scholar 

  52. Lanzi C et al. (2000) Inhibition of the transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative. Int J Cancer 85: 384–390

    CAS  PubMed  Google Scholar 

  53. Cuccuru G et al. (2004) Cellular effects and antitumor activity of the RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma. J Natl Cancer Inst 96: 1006–1014

    CAS  PubMed  Google Scholar 

  54. Bain J et al. (2003) The specificities of protein kinase inhibitors: an update. Biochem J 371: 199–204

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Carlomagno F et al. (2002) The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res 62: 1077–1082

    CAS  PubMed  Google Scholar 

  56. Carlomagno F et al. (2003) Efficient inhibition of RET/papillary thyroid carcinoma oncogenic kinases by 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). J Clin Endocrinol Metab 88: 1897–1902

    CAS  PubMed  Google Scholar 

  57. Melillo RM et al. (1999) Ret-mediated mitogenesis requires Src kinase activity. Cancer Res 59: 1120–1126

    CAS  PubMed  Google Scholar 

  58. Carniti C et al. (2003) PP1 inhibitor induces degradation of RETMEN2 A and RETMEN2B oncoproteins through proteosomal targeting. Cancer Res 63: 2234–2243

    CAS  PubMed  Google Scholar 

  59. Warmuth M et al. (2003) Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood 101: 664–672

    CAS  PubMed  Google Scholar 

  60. Heymach VJ (2005) ZD6474–clinical experience to date. Br J Cancer 92: S14–S20

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Carlomagno F et al. (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62: 7284–7290

    CAS  PubMed  Google Scholar 

  62. Vidal M et al. (2005) ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Res 65: 3538–3541

    CAS  PubMed  Google Scholar 

  63. Carlomagno F et al. (2004) Disease associated mutations at valine 804 of the RET receptor tyrosine kinase confer resistance to selective tyrosine kinase inhibitors. Oncogene 23: 6056–6063

    CAS  PubMed  Google Scholar 

  64. Carlomagno F and Santoro M (2005) Receptor tyrosine kinases as targets for anticancer therapeutics. Curr Med Chem 12: 1773–1781

    CAS  PubMed  Google Scholar 

  65. Strock CJ et al. (2003) CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res 63: 5559–5563

    CAS  PubMed  Google Scholar 

  66. Strock CJ et al. (2006) Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. J Clin Endocrinol Metab 91: 79–84

    CAS  PubMed  Google Scholar 

  67. Aggarwal S and Chu E (2005) Current therapies for advanced colorectal cancer. Oncology 19: 589–595

    PubMed  Google Scholar 

  68. Cohen MS et al. (2002) Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 132: 960–967

    PubMed  Google Scholar 

  69. Skinner MA et al. (2003) RET tyrosine kinase and medullary thyroid cells are unaffected by clinical doses of STI571. Anticancer Res 23: 3601–3606

    CAS  PubMed  Google Scholar 

  70. Ezzat S et al. (2005) Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth. Clin Cancer Res 11: 1336–1341

    CAS  PubMed  Google Scholar 

  71. Konstantinopoulos PA and Papavassiliou AG (2005) 17-AAG: mechanisms of antitumor activity. Expert Opin Investig Drugs 14: 1471–1474

    CAS  PubMed  Google Scholar 

  72. Wilhem SM et al. (2004) BAY 43-9006 exhibits a broad spectrum antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64: 7099–7109

    Google Scholar 

  73. Carlomagno et al. (2006) BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98: 326–334

    CAS  PubMed  Google Scholar 

  74. McKeage K and Perry CM (2002) Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs 62: 209–243

    CAS  PubMed  Google Scholar 

  75. Yano L et al (2000) Improved gene transfer to neuroblastoma cells by a monoclonal antibody targeting RET, a receptor tyrosine kinase. Hum Gene Ther 11: 995–1004

    CAS  PubMed  Google Scholar 

  76. Parthasarathy R et al. (1999) Hammerhead ribozyme-mediated inactivation of mutant RET in medullary thyroid carcinoma. Cancer Res 59: 3911–3914

    CAS  PubMed  Google Scholar 

  77. Hennige AM et al. (2001) Inhibition of RET oncogene activity by the protein tyrosine phosphatase SHP1. Endocrinology 142: 4441–4447

    CAS  PubMed  Google Scholar 

  78. Deininger M et al. (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105: 2640–2653

    CAS  PubMed  Google Scholar 

  79. Wells SA and Nevins JR (2004) Evolving strategies for targeted cancer therapy – past, present, and future. J Natl Cancer Inst 96: 980–981

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Brigitte M Pützer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drosten, M., Pützer, B. Mechanisms of Disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy. Nat Rev Clin Oncol 3, 564–574 (2006). https://doi.org/10.1038/ncponc0610

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncponc0610

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing