BAY 43-9006 inhibition of oncogenic RET mutants

Francesca Carlomagno, Suresh Anaganti, Teresa Guida, Giuliana Salvatore, Giancarlo Troncone, Scott M. Wilhelm, Massimo Santoro

Research output: Contribution to journalArticle

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 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific 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 fibroblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and flow 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 (IC50s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts 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 (IC50 = 110 nM, 95% confidence interval [CI] = 88 to 133 nM) or RET V804M (IC50 = 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 mm3 (difference = 28.5 mm3, 95% CI = 7 mm3 to 50 mm3), whereas in vehicle-treated mice (n = 7), mean tumor volume increased to 408 mm3 (difference = 320 mm3, 95% CI = 180 mm3 to 460 mm3; 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.

Original languageEnglish
Pages (from-to)326-334
Number of pages9
JournalJournal of the National Cancer Institute
Volume98
Issue number5
DOIs
Publication statusPublished - Mar 2006

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Phosphotransferases
Confidence Intervals
Inhibitory Concentration 50
Fibroblasts
Growth
Thyroid Neoplasms
Heterografts
Protein-Tyrosine Kinases
Alleles
Phospho-Specific Antibodies
sorafenib
Tumor Burden
Cell Size
Immunoblotting
Nude Mice
Urea
Neoplasms
Flow Cytometry
Thyroid Gland
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Carlomagno, F., Anaganti, S., Guida, T., Salvatore, G., Troncone, G., Wilhelm, S. M., & Santoro, M. (2006). BAY 43-9006 inhibition of oncogenic RET mutants. Journal of the National Cancer Institute, 98(5), 326-334. https://doi.org/10.1093/jnci/djj069

BAY 43-9006 inhibition of oncogenic RET mutants. / Carlomagno, Francesca; Anaganti, Suresh; Guida, Teresa; Salvatore, Giuliana; Troncone, Giancarlo; Wilhelm, Scott M.; Santoro, Massimo.

In: Journal of the National Cancer Institute, Vol. 98, No. 5, 03.2006, p. 326-334.

Research output: Contribution to journalArticle

Carlomagno, F, Anaganti, S, Guida, T, Salvatore, G, Troncone, G, Wilhelm, SM & Santoro, M 2006, 'BAY 43-9006 inhibition of oncogenic RET mutants', Journal of the National Cancer Institute, vol. 98, no. 5, pp. 326-334. https://doi.org/10.1093/jnci/djj069
Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM et al. BAY 43-9006 inhibition of oncogenic RET mutants. Journal of the National Cancer Institute. 2006 Mar;98(5):326-334. https://doi.org/10.1093/jnci/djj069
Carlomagno, Francesca ; Anaganti, Suresh ; Guida, Teresa ; Salvatore, Giuliana ; Troncone, Giancarlo ; Wilhelm, Scott M. ; Santoro, Massimo. / BAY 43-9006 inhibition of oncogenic RET mutants. In: Journal of the National Cancer Institute. 2006 ; Vol. 98, No. 5. pp. 326-334.
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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 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific 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 fibroblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and flow 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 (IC50s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts 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 (IC50 = 110 nM, 95{\%} confidence interval [CI] = 88 to 133 nM) or RET V804M (IC50 = 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 mm3 (difference = 28.5 mm3, 95{\%} CI = 7 mm3 to 50 mm3), whereas in vehicle-treated mice (n = 7), mean tumor volume increased to 408 mm3 (difference = 320 mm3, 95{\%} CI = 180 mm3 to 460 mm3; 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.",
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AU - Guida, Teresa

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AU - Troncone, Giancarlo

AU - Wilhelm, Scott M.

AU - Santoro, Massimo

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N2 - 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 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific 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 fibroblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and flow 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 (IC50s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts 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 (IC50 = 110 nM, 95% confidence interval [CI] = 88 to 133 nM) or RET V804M (IC50 = 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 mm3 (difference = 28.5 mm3, 95% CI = 7 mm3 to 50 mm3), whereas in vehicle-treated mice (n = 7), mean tumor volume increased to 408 mm3 (difference = 320 mm3, 95% CI = 180 mm3 to 460 mm3; 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.

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