RRC ID 71844
Author Bonaldi E, Gargiuli C, De Cecco L, Micali A, Rizzetti MG, Greco A, Borrello MG, Minna E.
Title BRAF Inhibitors Induce Feedback Activation of RAS Pathway in Thyroid Cancer Cells.
Journal Int J Mol Sci
Abstract BRAFV600E is the most frequent oncogenic mutation identified in papillary thyroid cancer (PTC). In PTC patients who do not respond to standard treatment, BRAF inhibitors are currently tested as alternative strategies. However, as observed for other targeted therapies, patients eventually develop drug resistance. The mechanisms of BRAF inhibitors response are still poorly understood in a thyroid cancer (TC) context. In this study, we investigated in BRAFV600E mutated TC cell lines the effects of Vemurafenib and Dabrafenib, two BRAF inhibitors currently used in a clinical setting. We assessed cell proliferation, and the expression and activity of the thyroid function related transporter NIS following the treatment with BRAF inhibitors. In addition, we investigated the global gene expression by microarray, the relevant modulated biological processes by gene set enrichment analysis (GSEA), and TC specific gene signatures related to MAPK pathway activation, thyroid differentiation, and transcriptional profile associated with BRAFV600E or RAS mutation. We found that both inhibitors induce antiproliferative and redifferentiative effects on TC cells, as well as a rewiring of the MAPK pathway related to RAS signaling. Our results suggest a possible mechanism of drug response to the BRAF inhibitors Vemurafenib or Dabrafenib, supporting very recent findings in TC patients treated with targeted therapies.
Volume 22(11)
Published 2021-5-27
DOI 10.3390/ijms22115744
PII ijms22115744
PMID 34072194
PMC PMC8198461
MeSH Biomarkers, Tumor Cell Line, Tumor Computational Biology / methods Dose-Response Relationship, Drug Drug Resistance, Neoplasm / genetics Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Mutation Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Proto-Oncogene Proteins B-raf / antagonists & inhibitors* Proto-Oncogene Proteins B-raf / genetics Proto-Oncogene Proteins B-raf / metabolism Signal Transduction / drug effects* Thyroid Neoplasms / drug therapy Thyroid Neoplasms / etiology Thyroid Neoplasms / metabolism* Thyroid Neoplasms / pathology Transcriptome ras Proteins / metabolism*
IF 4.556
Human and Animal Cells 8505C(RCB2103) HTC/C3(RCB0452) HOTHC(RCB0662)