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Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells
No full textAbstract Background BRAF inhibitors are effective anticancer agents in BRAF-mutated melanomas. By contrast, evidences about sensitivity of thyroid carcinomas to BRAF inhibition are conflicting and it has been proposed that BRAF V600E thyroid carcinoma cells are less sensitive to BRAF inhibitors due to activation of parallel signaling pathways. This study evaluated the hypothesis that feedback activation of EGFR signaling counteracts the cytostatic activity of vemurafenib (PLX4032) in BRAF V600E thyroid carcinoma cells. Methods Cell proliferation, cell cycle distribution, induction of apoptosis and EGFR and AKT signaling were evaluated in thyroid carcinoma cell lines bearing the BRAF V600E mutation in response to PLX4032. Results A partial and transient cytostatic response to PLX4032 was observed in thyroid carcinoma cell lines bearing the BRAF V600E mutation, with lack of full inhibition of ERK pathway. Interestingly, the exposure of thyroid carcinoma cells to PLX4032 resulted in a rapid feedback activation of EGFR signaling with parallel activation of AKT phosphorylation. Consistently, the dual inhibition of EGFR and BRAF, through combination therapy with PLX4032 and gefitinib, resulted in prevention of EGFR phosphorylation and sustained inhibition of ERK and AKT signaling and cell proliferation. Of note, the combined treatment with gefitinib and vemurafenib or the exposure of EGFR-silenced thyroid carcinoma cells to vemurafenib induced synthetic lethality compared to single agents. Conclusions These data suggest that the dual EGFR and BRAF blockade represents a strategy to by-pass resistance to BRAF inhibitors in thyroid carcinoma cells
Ottenimento e gestione di fonti primarie d’olivo in Basilicata: caratterizzazione varietale, diagnosi e protezione.
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Programmazione in silico di un sistema carrier per la produzione in pianta di un vaccino per il Virus dell'Influenza Aviaria.
No full textTRAP1 represents a key mediator of stemness and glycolytic metabolism in colorectal cancer cells.
No full textIn vitro stability of Cucumber mosaic virus nanoparticles carrying a Hepatitis C virus-derived epitope under simulated gastrointestinal conditions and in vivo efficacy of an edible vaccine
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