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Cancer Cell International
Published in: Cancer Cell International 1/2017

Open Access 01-12-2017 | Primary Research

Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells

Authors: Tiziana Notarangelo, Lorenza Sisinni, Valentina Condelli, Matteo Landriscina

Published in: Cancer Cell International | Issue 1/2017

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Abstract

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.
Appendix
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Metadata
Title
Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells
Authors
Tiziana Notarangelo
Lorenza Sisinni
Valentina Condelli
Matteo Landriscina
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2017
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-017-0457-z

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