Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants.

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Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F

Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants.

Clin Cancer Res. 2007 Jun 1;13(11):3363-9.

PubMed ID

17545544 [ View in PubMed

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Abstract

PURPOSE: Targeting of KIT and platelet-derived growth factor receptor (PDGFR) tyrosine kinases by imatinib is an effective anticancer strategy. However, mutations of the gatekeeper residue (T670 in KIT and T681 in PDGFRbeta) render the two kinases resistant to imatinib. The aim of this study was to evaluate whether sorafenib (BAY 43-9006), a multitargeted ATP-competitive inhibitor of KIT and PDGFR, was active against imatinib-resistant KIT and PDGFRbeta kinases. EXPERIMENTAL DESIGN: We used in vitro kinase assays and immunoblot with phosphospecific antibodies to determine the activity of sorafenib on KIT and PDGFRbeta kinases. We also exploited reporter luciferase assays to measure the effects of sorafenib on KIT and PDGFRbeta downstream signaling events. The activity of sorafenib on interleukin-3-independent proliferation of Ba/F3 cells expressing oncogenic KIT or its imatinib-resistant T670I mutant was also tested. RESULTS: Sorafenib efficiently inhibited gatekeeper mutants of KIT and PDGFRbeta (IC(50) for KIT T670I, 60 nmol/L; IC(50) for PDGFRbeta T681I, 110 nmol/L). Instead, it was less active against activation loop mutants of the two receptors (IC(50) for KIT D816V, 3.8 micromol/L; IC(50) for PDGFRbeta D850V, 1.17 micromol/L) that are also imatinib-resistant. Sorafenib blocked receptor autophosphorylation and signaling of KIT and PDGFRbeta gatekeeper mutants in intact cells as well as activation of AP1-responsive and cyclin D1 gene promoters, respectively. Finally, the compound inhibited KIT-dependent proliferation of Ba/F3 cells expressing the oncogenic KIT mutant carrying the T670I mutation. CONCLUSIONS: Sorafenib might be a promising anticancer agent for patients carrying KIT and PDGFRbeta gatekeeper mutations.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sorafenib	Mast/stem cell growth factor receptor Kit	Protein	Humans	Yes	Antagonist	Details
Sorafenib	Platelet-derived growth factor receptor beta	Protein	Humans	Yes	Inhibitor	Details