CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res 2003 Sep 01;63(17):5559-63
Date
09/23/2003Pubmed ID
14500395Scopus ID
2-s2.0-0141592764 (requires institutional sign-in at Scopus site) 91 CitationsAbstract
All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and approximately 40% of the sporadic cases of MTC, the RET kinase is constitutively activated by mutation. This suggests that RET may be an effective therapeutic target for treatment of MTC. We show that the indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET in MTC cells. These compounds effectively inhibit RET phosphorylation in a dose-dependent manner at concentrations <100 nM in 0.5% serum and at somewhat higher concentrations in the presence of 16% serum. They also blocked the growth of these MTC cells in culture. CEP-751 and its prodrug, CEP-2563, also inhibited tumor growth in MTC cell xenografts. These results show that inhibiting RET can block the growth of MTC cells and may have a therapeutic benefit in MTC.
Author List
Strock CJ, Park JI, Rosen M, Dionne C, Ruggeri B, Jones-Bolin S, Denmeade SR, Ball DW, Nelkin BDAuthor
Jong-In Park PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCarbazoles
Carcinoma, Medullary
Cell Division
Dose-Response Relationship, Drug
Enzyme Inhibitors
Furans
Growth Inhibitors
Humans
Indoles
Male
Mice
Mice, Nude
Multiple Endocrine Neoplasia Type 2b
Mutation
Oncogene Proteins
Phosphorylation
Prodrugs
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases
Thyroid Neoplasms
Tumor Cells, Cultured
Xenograft Model Antitumor Assays