CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth

Christopher J. Strock, Jong In Park, Mark Rosen, Craig Dionne, Bruce Ruggeri, Susan Jones-Bolin, Samuel R. Denmeade, Douglas W. Ball, Barry D. Nelkin

Research output: Contribution to journalArticle

Abstract

All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and ∼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.

Original languageEnglish (US)
Pages (from-to)5559-5563
Number of pages5
JournalCancer Research
Volume63
Issue number17
StatePublished - Sep 1 2003

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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