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Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
BAY 43-9006 inhibition of oncogenic RET mutants
Francesca Carlomagno1, Suresh Anaganti, Teresa Guida
1Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy.
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.
Insights
BAY 43-9006 effectively inhibits oncogenic RET kinase activity and blocks the growth of thyroid cancer cells, including those with drug-resistant mutations. This suggests its potential as a therapeutic agent for RET-positive thyroid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Medullary and papillary thyroid carcinomas frequently exhibit oncogenic RET tyrosine kinase activation.
- The biaryl urea BAY 43-9006 is a known inhibitor of various tyrosine kinases.
- This study investigates BAY 43-9006's efficacy against RET kinase and its oncogenic activity.
Purpose of the Study:
- To evaluate the inhibitory effect of BAY 43-9006 on oncogenic RET kinase function.
- To assess the impact of BAY 43-9006 on the proliferation of thyroid carcinoma cells with oncogenic RET.
- To determine the therapeutic potential of BAY 43-9006 against RET-positive thyroid tumors, including resistant mutations.
Main Methods:
- In vitro kinase assays and immunoblotting were used to assess BAY 43-9006 activity against oncogenic RET.
- Cell proliferation was measured using growth curves and flow cytometry in various cancer cell lines and fibroblasts.
- Tumor growth was evaluated in xenograft models using BAY 43-9006 treatment in athymic mice.
Main Results:
- BAY 43-9006 demonstrated potent inhibition of oncogenic RET kinase activity (IC50 ≤ 50 nM).
- The compound arrested the proliferation of RET-driven thyroid carcinoma cells and fibroblasts, including those with resistant V804L and V804M mutations.
- In vivo, BAY 43-9006 treatment significantly reduced TT cell xenograft tumor volume in mice, correlating with decreased RET phosphorylation.
Conclusions:
- BAY 43-9006 is a potent inhibitor of the RET kinase.
- The drug shows promise as a therapeutic agent for RET-positive thyroid tumors, including those with V804 mutations.
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