Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma
| Autor: | Qin Liu, Patricia Reyes-Uribe, Tona M. Gilmer, Douglas J. DeMarini, Melissa Wilson, Bin Li, Adina Vultur, Meenhard Herlyn, Rolf Swoboda, Hsin-Yi Chen, Mizuho Fukunaba-Kalabis, Jeffrey R. Infante, Anne-Marie Martin, Thomas Y. Chen, Ronen Marmorstein, Jessie Villanueva, Clemens Krepler, David C. Schultz, Minu Samanta, Lynn M. Schuchter, Wei Xu, Katrin Sproesser, Xiaowei Xu, Bradley Wubbenhorst, Ravi K. Amaravadi, Katherine L. Nathanson, Giorgos C. Karakousis, David W. Speicher |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Models Molecular Proto-Oncogene Proteins B-raf MAPK/ERK pathway endocrine system diseases MAP Kinase Kinase 2 P70-S6 Kinase 1 Drug resistance Biology Article General Biochemistry Genetics and Molecular Biology Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans Extracellular Signal-Regulated MAP Kinases Melanoma Protein Kinase Inhibitors neoplasms lcsh:QH301-705.5 PI3K/AKT/mTOR pathway 030304 developmental biology Trametinib 0303 health sciences Ribosomal Protein S6 Kinases MEK inhibitor Gene Amplification Dabrafenib Middle Aged medicine.disease digestive system diseases 3. Good health enzymes and coenzymes (carbohydrates) lcsh:Biology (General) Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cancer research medicine.drug |
| Zdroj: | Cell Reports, Vol 4, Iss 6, Pp 1090-1099 (2013) |
| ISSN: | 2211-1247 |
| Popis: | SummaryAlthough BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it. |
| Databáze: | OpenAIRE |
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