Targeting RET receptor tyrosine kinase activation in cancer.

Abstract

After ligand binding induces dimerization, the RET receptor tyrosine kinase activates multiple signal transduction pathways. Constitutively activating mutations and chromosomal rearrangements are the primary oncogenic event in a significant number of medullary thyroid cancers (MTC) and papillary thyroid cancers (PTC), respectively. When specific germline mutations in RET are identified early, prophylactic thyroidectomy can be timed to remove at-risk tissue in patients with multiple endocrine neoplasia 2 (MEN2) syndromes who would otherwise develop MTC. Conventional therapy for progressive metastatic MTC is limited. Small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations, including RET, and have shown efficacy against a variety of malignancies. Initial clinical evidence suggests that several of these inhibitors, including sorafenib, vandetanib, motesanib, sunitinib, and XL-184, may have some benefit in treating progressive MTC. Although initial success seen in these trials seems to be modest, it represents a major breakthrough in the treatment of patients with widespread metastatic MTC.

• Authors: John E Phay, Manisha H Shah
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 24 Pg. 5936-41 (Dec 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20930041 (Publication Type: Journal Article, Review)
• Copyright: ©2010 AACR.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-ret
• RET protein, human
• Receptor Protein-Tyrosine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Medullary (diagnosis, drug therapy, genetics, metabolism)
• Enzyme Activation (drug effects, physiology)
• Genetic Association Studies
• Humans
• Models, Biological
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-ret (antagonists & inhibitors, genetics)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Thyroid Neoplasms (diagnosis, drug therapy, genetics, metabolism)