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:

Multikinase inhibitors: a new option for the treatment of thyroid cancer

Abstract

Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation and treatment with TSH-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Activation of mitogenic and angiogenic signaling pathways occurs in these cancers, and preclinical models have shown that inhibition of key kinase steps in these pathways can have antitumoral effects. Several of these kinase inhibitors have now been tested in phase II and phase III trials, with modestly encouraging results. Some promising data exist for the use of vandetanib (also known as ZD6474), motesanib, axitinib, cabozantinib (also known as XL184), sorafenib, sunitinib, pazopanib and lenvatinib (also known as E7080) in progressive thyroid cancer of medullary, papillary and follicular subtypes. These drugs are generally well-tolerated, although dose-limiting toxicities are common, and a few (probable) treatment-related deaths have been reported. Additional phase III trials will be needed to conclusively show that treatment benefit exceeds risk. Drug resistance can occur via activation of alternate mitogenic signals (pathway switching), as has been reported for the use of kinase inhibitors in other malignancies, such as melanoma. The hypothesis that combinations of kinase inhibitors targeting different pathways might produce better results is currently being tested in several clinical trials.

Key Points

  • Only one phase III trial of kinase inhibitors in patients with thyroid cancer, using vandetanib in progressive medullary thyroid cancer, has been completed to date

  • Patients with progressive medullary or differentiated thyroid cancer should be enrolled in ongoing clinical trials of kinase inhibitors

  • In the absence of clinical trial data, 'off-label' use of registered kinase inhibitors should be considered

  • Patients receiving kinase inhibitors should be carefully monitored for serious adverse events, including hand–foot syndrome, hypertension, perforated viscus, tumor bleeding, keratoacanthoma and hypothyroidism

  • Some kinase inhibitors are selective for particular cancer genotypes (for example, vemurafenib in melanoma patients with the BRAF Val600Glu amino acid substitution), but more research is needed before molecular testing becomes routine

  • The levels of classic tumor biomarkers, such as calcitonin or thyroglobulin, generally decrease with treatment, but correlation with radiological responses has not always been demonstrated; new biomarkers, such as soluble VEGFRs, are being evaluated

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: Schematic diagram of the kinase signaling cascade involved in thyroid tumorigenesis.

Similar content being viewed by others

References

  1. National Cancer Institute. Surveillance Epidemiology and End Results [online], (2011).

  2. DeLellis, R. A., Lloyd, R. V., Heitz, P. U. & Eng, C. (Eds) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. (IARC Press, Lyon, 2004).

    Google Scholar 

  3. Mazzaferri, E. L. & Jhiang, S. M. Differentiated thyroid cancer long-term impact of initial therapy. Trans. Am. Clin. Climatol. Assoc. 106, 151–168 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Eustatia-Rutten, C. F. et al. Survival and death causes in differentiated thyroid carcinoma. J. Clin. Endocrinol. Metab. 91, 313–319 (2006).

    Article  CAS  Google Scholar 

  5. Dohan, O. et al. The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr. Rev. 24, 48–77 (2003).

    Article  CAS  Google Scholar 

  6. Dancey, J. & Sausville, E. A. Issues and progress with protein kinase inhibitors for cancer treatment. Nat. Rev. Drug Discovery 2, 296–313 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Learoyd, D. L., Messina, M., Zedenius, J. & Robinson, B. G. Molecular genetics of thyroid tumors and surgical decision-making. World J. Surg. 24, 923–933 (2000).

    Article  CAS  Google Scholar 

  9. Kondo, T., Ezzat, S. & Asa, S. L. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat. Rev. Cancer 6, 292–306 (2006).

    Article  CAS  Google Scholar 

  10. Fusco, A. et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 328, 170–172 (1987).

    Article  CAS  Google Scholar 

  11. Xing, M. BRAF mutation in thyroid cancer. Endocr. Relat. Cancer 12, 245–262 (2005).

    Article  CAS  Google Scholar 

  12. Ricarte-Filho, J. C. et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 69, 4885–4893 (2009).

    Article  CAS  Google Scholar 

  13. Wang, Y. et al. High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors. J. Clin. Endocrinol. Metab. 92, 2387–2390 (2007).

    Article  CAS  Google Scholar 

  14. Segouffin-Cariou, C. & Billaud, M. Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J. Biol. Chem. 275, 3568–3576 (2000).

    Article  CAS  Google Scholar 

  15. Diallo-Krou, E. et al. Paired box gene 8-peroxisome proliferator-activated receptor-γ fusion protein and loss of phosphatase and tensin homolog synergistically cause thyroid hyperplasia in transgenic mice. Endocrinology 150, 5181–5190 (2009).

    Article  CAS  Google Scholar 

  16. Verfaillie, C. M. Biology of chronic myelogenous leukemia. Hematol. Oncol. Clin. North Am. 12, 1–29 (1998).

    Article  CAS  Google Scholar 

  17. Stein, B. et al. Treatment options for patients with chronic myeloid leukemia who are resistant to or unable to tolerate imatinib. Clinical Therapeutics 32, 804–820 (2010).

    Article  CAS  Google Scholar 

  18. Hochhaus, A. et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109, 2303–2309 (2007).

    Article  CAS  Google Scholar 

  19. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Article  CAS  Google Scholar 

  20. Smalley, K. S. & Sondak, V. K. Melanoma—an unlikely poster child for personalized cancer therapy. N. Engl. J. Med. 363, 876–878 (2010).

    Article  CAS  Google Scholar 

  21. Wellbrock, C. et al. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. Plos ONE 3, e2734 (2008).

    Article  Google Scholar 

  22. Hoeflich, K. P. et al. Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res. 66, 999–1006 (2006).

    Article  CAS  Google Scholar 

  23. Livingstone, E., Zimmer, L., Piel, S. & Schadendorf, D. PLX4032: does it keep its promise for metastatic melanoma treatment? Expert Opin. Investig. Drugs 19, 1439–1449 (2010).

    Article  CAS  Google Scholar 

  24. Hauschild, A. et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J. Clin. Oncol. 27, 2823–2830 (2009).

    Article  CAS  Google Scholar 

  25. Smalley, K. S. PLX-4032, a small molecule B-Raf inhibitor for the potential treatment of malignant melanoma. Curr. Opin. Investig. Drugs 11, 699–706 (2010).

    CAS  PubMed  Google Scholar 

  26. Flaherty, K. et al. Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer [abstract]. J. Clin. Oncol. 27 (Suppl.), a9000 (2009).

    Google Scholar 

  27. Flaherty, K. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    Article  CAS  Google Scholar 

  28. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  Google Scholar 

  29. Heidorn, S. J. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209–221 (2010).

    Article  CAS  Google Scholar 

  30. Adjei, A. A. et al. Phase I pharmokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J. Clin. Oncol. 26, 2139–2146 (2008).

    Article  CAS  Google Scholar 

  31. Infante, J. R. et al. Safety and efficacy results from the first-in-human study of the oral MEK1/2 inhibitor GSK1120212 [abstract]. J. Clin. Oncol. 28, a2503 (2010).

    Article  Google Scholar 

  32. Infante, J. R. et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436) [abstract]. J. Clin. Oncol. 29, a8503 (2011).

    Article  Google Scholar 

  33. Kaplan, F. M., Shao, Y., Mayberry, M. M & Aplin, A. E. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene 30, 366–371 (2011).

    Article  CAS  Google Scholar 

  34. Sherman, S. I. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J. Clin. Endocrinol. Metab. 94, 1493–1499 (2009).

    Article  CAS  Google Scholar 

  35. Perez, C. A., Santos, E. S., Arango, B. A., Raez, L. E. & Cohen, E. E. Novel molecular targeted therapies for refractory thyroid cancer. Head Neck doi:10.1002/hed.21755.

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

    CAS  PubMed  Google Scholar 

  37. Vitagliano, D. et al. The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells. Endocr. Relat. Cancer 18, 1–11 (2011).

    Article  CAS  Google Scholar 

  38. Akeno-Stuart, N. et al. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res. 67, 6956–6964 (2007).

    Article  CAS  Google Scholar 

  39. Koga, K. et al. Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis. Cancer Sci. 101, 941–947 (2010).

    Article  CAS  Google Scholar 

  40. Henderson, Y. C. et al. Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement. Clin. Cancer Res. 14, 4908–4914 (2008).

    Article  CAS  Google Scholar 

  41. Carlomagno, F. et al. BAY 43–9006 inhibition of oncogenic RET mutants. J. Natl Cancer Inst. 98, 326–334 (2006).

    Article  CAS  Google Scholar 

  42. Verbeek, H. H. et al. The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. J. Clin. Endocrinol. Metab. 96, E991–E995 (2011).

    Article  CAS  Google Scholar 

  43. Wells, S. A. Jr et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J. Clin. Oncol. 28, 767–772 (2010).

    Article  CAS  Google Scholar 

  44. Robinson, B. G., Paz-Ares, L., Krebs, A., Vasselli, J. & Haddad, R. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J. Clin. Endocrinol. Metab. 95, 2664–2671 (2010).

    Article  CAS  Google Scholar 

  45. Wells, S. A. Jr et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): a randomized, double-blind phase III trial (ZETA) [abstract]. J. Clin. Oncol. 28, a5503 (2010).

    Article  Google Scholar 

  46. Polverino, A. 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 Res. 66, 8715–8721 (2006).

    Article  CAS  Google Scholar 

  47. Schlumberger, M. J. et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J. Clin. Oncol. 27, 3794–3801 (2009).

    Article  CAS  Google Scholar 

  48. Cohen, E. E. et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J. Clin. Oncol. 26, 4708–4713 (2008).

    Article  CAS  Google Scholar 

  49. Lam, E. T. et al. Phase II clinical triial of sorafenib in metastatic medullary thyroid cancer. J. Clin. Oncol. 28, 2323–2330 (2010).

    Article  CAS  Google Scholar 

  50. Kurzrock, R. et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J. Clin. Oncol. 29, 2660–2666 (2011).

    Article  CAS  Google Scholar 

  51. Liu, D. & Xing, M. Potent inhibition of thyroid cancer cells by the MEK inhibitor PD0325901 and its potentiation by suppression of the PI3K and NF-κB pathways. Thyroid 18, 853–864 (2008).

    Article  Google Scholar 

  52. Liu, D., Xing, J., Trink, B. & Xing, M. BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus. Int. J. Cancer 127, 2965–2973 (2010).

    Article  CAS  Google Scholar 

  53. Salvatore, G. et al. BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin. Cancer Res. 12, 1623–1629 (2006).

    Article  CAS  Google Scholar 

  54. Henderson, Y. C., Ahn, S. H., Kang, Y. & Clayman, G. L. Sorafenib potently inhibits papillary thyroid carcinomas harbouring RET/PTC1 rearrangement. Clin. Cancer Res. 14, 4908–4914 (2008).

    Article  CAS  Google Scholar 

  55. Liu, R. et al. The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. J. Clin. Endocrinol. Metab. 96, E577–E585 (2011).

    Article  CAS  Google Scholar 

  56. Liu, D., Xing, J., Trink, B. & Xing, M. BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus. Int. J. Cancer 127, 2965–2973 (2010).

    Article  CAS  Google Scholar 

  57. Jin, N., Jiang, T., Rosen, D. M., Nelkin, B. D. & Ball, D. W. Dual inhibition of mitogen-activated protein kinase kinase and mammalian target of rapamycin in differentiated and anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 94, 4107–4112 (2009).

    Article  CAS  Google Scholar 

  58. Xing, J., Liu, R., Xing, M. & Trink, B. The BRAF T1799A mutation confers sensitivity of thyroid cancer cells to the BRAF V600E inhibitor PLX4032 (RG7204). Biochem. Biophys. Res. Commun. 404, 958–962 (2011).

    Article  CAS  Google Scholar 

  59. Sherman, S. I. et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N. Engl. J. Med. 359, 31–42 (2008).

    Article  CAS  Google Scholar 

  60. Bass, M. B. et al. Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer. J. Clin. Endocrinol. Metab. 2010, 5018–5027 (2010).

    Article  Google Scholar 

  61. Kloos, R. T. et al. Phase II trial of sorafenib in metastatic thyroid cancer. J. Clin. Oncol. 27, 1675–1684 (2009).

    Article  CAS  Google Scholar 

  62. Gupta-Abramson, V. et al. Phase II trial of sorafenib in advanced thyroid cancer. J. Clin. Oncol. 26, 4714–4719 (2008).

    Article  CAS  Google Scholar 

  63. Ahmed, M. et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer—a phase II study in a UK based population. Eur. J. Endocrinol. 165, 315–322 (2011).

    Article  CAS  Google Scholar 

  64. Cabanillas, M. E. et al. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J. Clin. Endocrinol. Metab. 95, 2588–2595 (2010).

    Article  CAS  Google Scholar 

  65. Carr, L. L. et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin. Cancer Res. 16, 5260–5268 (2010).

    Article  CAS  Google Scholar 

  66. Bible, K. C. et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 11, 962–972 (2010).

    Article  CAS  Google Scholar 

  67. Sherman, S. I. et al. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) [abstract]. J. Clin. Oncol. 29, a5503 (2011).

    Article  Google Scholar 

  68. Riesco-Eizaguirre, G., Gutiérrez-Martínez, P., García-Cabezas, M. A., Nistal, M. & Santisteban, P. The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr. Relat. Cancer 13, 257–269 (2006).

    Article  CAS  Google Scholar 

  69. Hoftijzer, H. et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake in patients with differentiated thyroid cancer. Eur. J. Endocrinol. 161, 923–931 (2009).

    Article  CAS  Google Scholar 

  70. Hong, D. S. et al. Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies. J. Clin. Endocrinol. Metab. 96, 997–1005 (2011).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors researched the data for the article and reviewed and/or edited the manuscript before submission. M. L. Gild, M. Bullock and R. Clifton-Bligh provided a substantial contribution to discussions of the content and contributed equally to writing the article.

Corresponding author

Correspondence to Roderick Clifton-Bligh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gild, M., Bullock, M., Robinson, B. et al. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol 7, 617–624 (2011). https://doi.org/10.1038/nrendo.2011.141

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.141

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