Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo
| Autor: | Sharon Sams, Laura A. Pike, Veronica L Espinoza, Christopher D. Raeburn, Philip Reigan, Rebecca E. Schweppe, Daniel V. LaBarbera, Nikita Pozdeyev, Hannah M Hicks, Logan R McKenna |
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| Rok vydání: | 2021 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway Cancer Research Indazoles endocrine system diseases MAP Kinase Signaling System Mice Nude Apoptosis Biology Piperazines chemistry.chemical_compound In vivo Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Oximes medicine Animals Humans Thyroid Neoplasms Anaplastic thyroid cancer Protein Kinase Inhibitors neoplasms Molecular Biology Thyroid cancer Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Imidazoles Drug Synergism Dabrafenib medicine.disease Xenograft Model Antitumor Assays digestive system diseases In vitro chemistry Drug Resistance Neoplasm Mutation Cancer research Female Growth inhibition medicine.drug |
| Zdroj: | Molecular Carcinogenesis. 60:201-212 |
| ISSN: | 1098-2744 0899-1987 |
| Popis: | Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF-directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single-agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF-mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients. |
| Databáze: | OpenAIRE |
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