BRAF Inhibitors Induce Feedback Activation of RAS Pathway in Thyroid Cancer Cells

Autor: Loris De Cecco, Elisa Bonaldi, Emanuela Minna, Arianna Micali, Angela Greco, Maria Grazia Rizzetti, Maria Grazia Borrello, Chiara Gargiuli
Jazyk: angličtina
Rok vydání: 2021
Předmět:
MAPK/ERK pathway
endocrine system diseases
Papillary thyroid cancer
Biology (General)
Vemurafenib
Thyroid cancer
Spectroscopy
BRAFV600E
Thyroid
BRAF inhibitors
General Medicine
Computer Science Applications
Gene Expression Regulation
Neoplastic
Chemistry
medicine.anatomical_structure
thyroid cancer cell
Thyroid function
medicine.drug
Signal Transduction
Proto-Oncogene Proteins B-raf
QH301-705.5
Context (language use)
Catalysis
Article
Inorganic Chemistry
Cell Line
Tumor
medicine
Biomarkers
Tumor
Humans
cell signaling
Thyroid Neoplasms
Physical and Theoretical Chemistry
Molecular Biology
Protein Kinase Inhibitors
neoplasms
QD1-999
Dose-Response Relationship
Drug
business.industry
Gene Expression Profiling
Organic Chemistry
Computational Biology
Dabrafenib
medicine.disease
digestive system diseases
Drug Resistance
Neoplasm
Mutation
Cancer research
ras Proteins
business
Transcriptome
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 5744, p 5744 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 11
ISSN: 1661-6596
1422-0067
Popis: 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.
Databáze: OpenAIRE
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