Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer

Autor: Gideon Bollag, Jack Lawler, Paul S. Lin, Matthew A. Nehs, Sareh Parangi, Richard A. Hodin, Sushruta S. Nagarkatti, Andrew H. Fischer, Carmelo Nucera, Michal Mekel, Peter M. Sadow
Rok vydání: 2011
Předmět:
Male
Cancer Research
Indoles
endocrine system diseases
Anaplastic thyroid cancer
Mice
SCID
medicine.disease_cause
Mass Spectrometry
Metastasis
Papillary thyroid cancer
Orthotopic
Mice
0302 clinical medicine
Endocrinology
Invasion
Cell Movement
Phosphorylation
Mitogen-Activated Protein Kinase 1
0303 health sciences
Mutation
Sulfonamides
Mitogen-Activated Protein Kinase 3
Transfection
3. Good health
Primary human normal thyroid follicular cells
Oncology
030220 oncology & carcinogenesis
Female
Proto-Oncogene Proteins B-raf
endocrine system
Genotype
Down-Regulation
Cell Growth Processes
BRAFV600E inhibitor
03 medical and health sciences
Downregulation and upregulation
Cell Line
Tumor
medicine
Animals
Humans
Thyroid Neoplasms
030304 developmental biology
business.industry
Cancer
medicine.disease
Xenograft Model Antitumor Assays
Cell culture
Cancer research
business
Zdroj: The Oncologist
ISSN: 1549-490X
Popis: The role of the B-RafV600E mutation in aggressive thyroid cancers is examined.
Purpose. B-RafV600E may play a role in the progression from papillary thyroid cancer to anaplastic thyroid cancer (ATC). We tested the effects of a highly selective B-RafV600E inhibitor, PLX4720, on proliferation, migration, and invasion both in human thyroid cancer cell lines (8505cB-RafV600E and TPC-1RET/PTC-1 and wild-type B-Raf) and in primary human normal thyroid (NT) follicular cells engineered with or without B-RafV600E. Experimental Design. Large-scale genotyping analysis by mass spectrometry was performed in order to analyze >900 gene mutations. Cell proliferation and migration/invasion were performed upon PLX4720 treatment in 8505c, TPC-1, and NT cells. Orthotopic implantation of either 8505c or TPC-1 cells into the thyroid of severe combined immunodeficient mice was performed. Gene validations were performed by quantitative polymerase chain reaction and immunohistochemistry. Results. We found that PLX4720 reduced in vitro cell proliferation and migration and invasion of 8505c cells, causing early downregulation of genes involved in tumor progression. PLX4720-treated NT cells overexpressing B-RafV600E (heterozygous wild-type B-Raf/B-RafV600E) showed significantly lower cell proliferation, migration, and invasion. PLX4720 treatment did not block cell invasion in TPC-1 cells with wild-type B-Raf, which showed very low and delayed in vivo tumor growth. In vivo, PLX4720 treatment of 8505c orthotopic thyroid tumors inhibited tumor aggressiveness and significantly upregulated the thyroid differentiation markers thyroid transcription factor 1 and paired box gene 8. Conclusions. Here, we have shown that PLX4720 preferentially inhibits migration and invasion of B-RafV600E thyroid cancer cells and tumor aggressiveness. Normal thyroid cells were generated to be heterozygous for wild-type B-Raf/B-RafV600E, mimicking the condition found in most human thyroid cancers. PLX4720 was effective in reducing cell proliferation, migration, and invasion in this heterozygous model. PLX4720 therapy should be tested and considered for a phase I study for the treatment of patients with B-RafV600E ATC.
Databáze: OpenAIRE
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