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- W4377011706 abstract "B-raf inhibitors (BRAFi) are effective for BRAF-mutated papillary (PTC) and anaplastic (ATC) thyroid carcinomas, although acquired resistance impairs tumour cells' sensitivity and/or limits drug efficacy. Targeting metabolic vulnerabilities is emerging as powerful approach in cancer.In silico analyses identified metabolic gene signatures and Hif-1α as glycolysis regulator in PTC. BRAF-mutated PTC, ATC and control thyroid cell lines were exposed to HIF1A siRNAs or chemical/drug treatments (CoCl2, EGF, HGF, BRAFi, MEKi and diclofenac). Genes/proteins expression, glucose uptake, lactate quantification and viability assays were used to investigate the metabolic vulnerability of BRAF-mutated cells.A specific metabolic gene signature was identified as a hallmark of BRAF-mutated tumours, which display a glycolytic phenotype, characterised by enhanced glucose uptake, lactate efflux and increased expression of Hif-1α-modulated glycolytic genes. Indeed, Hif-1α stabilisation counteracts the inhibitory effects of BRAFi on these genes and on cell viability. Interestingly, targeting metabolic routes with BRAFi and diclofenac combination we could restrain the glycolytic phenotype and synergistically reduce tumour cells' viability.The identification of a metabolic vulnerability of BRAF-mutated carcinomas and the capacity BRAFi and diclofenac combination to target metabolism open new therapeutic perspectives in maximising drug efficacy and reducing the onset of secondary resistance and drug-related toxicity." @default.
- W4377011706 created "2023-05-19" @default.
- W4377011706 creator A5002139121 @default.
- W4377011706 creator A5009911982 @default.
- W4377011706 creator A5028820532 @default.
- W4377011706 creator A5040413827 @default.
- W4377011706 creator A5059827878 @default.
- W4377011706 creator A5087786651 @default.
- W4377011706 date "2023-05-17" @default.
- W4377011706 modified "2023-10-14" @default.
- W4377011706 title "Targeting metabolism by B-raf inhibitors and diclofenac restrains the viability of BRAF-mutated thyroid carcinomas with Hif-1α-mediated glycolytic phenotype" @default.
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