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BAY 43-9006 inhibition of oncogenic RET mutants
- Source :
- Journal of the National Cancer Institute, 98 (2006): 326–334. doi:10.1093/jnci/djj069, info:cnr-pdr/source/autori:Carlomagno F; Anaganti S; Guida T; Salvatore G; Troncone G; Wilhelm SM; Santoro M./titolo:BAY 43-9006 inhibition of oncogenic RET mutants./doi:10.1093%2Fjnci%2Fdjj069/rivista:Journal of the National Cancer Institute (Print)/anno:2006/pagina_da:326/pagina_a:334/intervallo_pagine:326–334/volume:98
- Publication Year :
- 2006
-
Abstract
- Background : Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. Methods : We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fi broblasts by using immunocomplex kinase assays and immunoblotting with phospho-specifi c antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fi broblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and fl ow cytometry. Growth of TT cell – derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. Results : BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC 50 s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fi broblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC 50 = 110 nM, 95% confi dence interval [CI] = 88 to 133 nM) or RET V804M (IC 50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts ( n = 7) was reduced from 72.5 to 44 mm 3 (difference = 28.5 mm 3 , 95% CI = 7 mm 3 to 50 mm 3 ), whereas in vehicle-treated mice ( n = 7), mean tumor volume increased to 408 mm 3 (difference = 320 mm 3 , 95% CI = 180 mm 3 to 460 mm 3 ; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. Conclusions : BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study. [J Natl Cancer Inst 2006;98:326 – 34]
- Subjects :
- Sorafenib
Niacinamide
Cancer Research
medicine.medical_specialty
endocrine system
endocrine system diseases
Pyridines
Immunoblotting
Transplantation, Heterologous
Administration, Oral
Mice, Nude
Antineoplastic Agents
Biology
Transfection
Drug Administration Schedule
thyroid
Inhibitory Concentration 50
Mice
Internal medicine
medicine
Animals
cancer
Thyroid Neoplasms
Kinase activity
Tyrosine
Enzyme Inhibitors
Phosphorylation
Thyroid cancer
therapy
Kinase
Phenylurea Compounds
Benzenesulfonates
Cell Cycle
Phosphotransferases
Proto-Oncogene Proteins c-ret
Fibroblasts
medicine.disease
Molecular biology
Transplantation
Endocrinology
Oncology
RET
thyroid cancer
Mutation
NIH 3T3 Cells
Tyrosine kinase
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Journal of the National Cancer Institute, 98 (2006): 326–334. doi:10.1093/jnci/djj069, info:cnr-pdr/source/autori:Carlomagno F; Anaganti S; Guida T; Salvatore G; Troncone G; Wilhelm SM; Santoro M./titolo:BAY 43-9006 inhibition of oncogenic RET mutants./doi:10.1093%2Fjnci%2Fdjj069/rivista:Journal of the National Cancer Institute (Print)/anno:2006/pagina_da:326/pagina_a:334/intervallo_pagine:326–334/volume:98
- Accession number :
- edsair.doi.dedup.....2b8a162bb1fa9e5e1f54dbee6a22e58e