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

• Published in: International journal of molecular sciences Vol. 22; no. 11; p. 5744
• Main Authors: Bonaldi, Elisa, Gargiuli, Chiara, De Cecco, Loris, Micali, Arianna, Rizzetti, Maria Grazia, Greco, Angela, Borrello, Maria Grazia, Minna, Emanuela
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-05-2021; MDPI
• Subjects: Biological activity; Biomarkers, Tumor; BRAF inhibitors; BRAFV600E; Cancer therapies; Care and treatment; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; cell signaling; Computational Biology - methods; Development and progression; DNA microarrays; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Neoplasm - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene set enrichment analysis; Genes; Genetic aspects; Genetic research; Genetic transcription; Humans; Inhibitors; Iodine; Kinases; MAP kinase; Medical research; Medicine, Experimental; Mutation; Papillary thyroid cancer; Patients; 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; ras Proteins - metabolism; Scientific equipment and supplies industry; Signal Transduction - drug effects; Thyroid cancer; thyroid cancer cell; Thyroid gland; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - etiology; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Transcription activation; Transcriptome; Tumors; Vemurafenib; Serbia; United States; BRAFV600E; thyroid cancer cell; BRAF inhibitors; cell signaling
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22115744

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
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
or
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.