Regulating the response to targeted MEK inhibition in melanoma
| Autor: | William H. Conrad, Randall T. Moon, Rima M. Kulikauskas, Travis L. Biechele, Andy J. Chien, Reyna D. Swift |
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| Rok vydání: | 2012 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway Neuroblastoma RAS viral oncogene homolog Indoles Antineoplastic Agents Apoptosis Biology Proto-Oncogene Proteins p21(ras) Axin Protein Cell Line Tumor Wnt3A Protein medicine Humans RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Melanoma neoplasms Molecular Biology beta Catenin Sulfonamides Extra Views Wnt signaling pathway Cell Biology medicine.disease Cell biology Gene Expression Regulation Neoplastic Catenin Mutation Cancer research Benzimidazoles Signal transduction WNT3A Signal Transduction Developmental Biology |
| Zdroj: | Cell Cycle. 11:3724-3730 |
| ISSN: | 1551-4005 1538-4101 |
| Popis: | The limitations of revolutionary new mutation-specific inhibitors of BRAF(V600E) include the universal recurrence seen in melanoma patients treated with this novel class of drugs. Recently, our lab showed that simultaneous activation of the Wnt/β-catenin signaling pathway and targeted inhibition of BRAF(V600E) by PLX4720 synergistically induces apoptosis across a spectrum of BRAF(V600E) melanoma cell lines. As a follow-up to that study, treatment of BRAF-mutant and NRAS-mutant melanoma lines with WNT3A and the MEK inhibitor AZD6244 also induces apoptosis. The susceptibility of BRAF-mutant lines and NRAS-mutant lines to apoptosis correlates with negative regulation of Wnt/β-catenin signaling by ERK/MAPK signaling and dynamic decreases in abundance of the downstream scaffolding protein, AXIN1. Apoptosis-resistant NRAS-mutant lines can sensitize to AZD6244 by pretreatment with AXIN1 siRNA, similar to what we previously reported in BRAF-mutant cell lines. Taken together, these findings indicate that NRAS-mutant melanoma share with BRAF-mutant melanoma the potential to regulate apoptosis upon MEK inhibition through WNT3A and dynamic regulation of cellular AXIN1. Understanding the cellular context that makes melanoma cells susceptible to this combination treatment will contribute to the study and development of novel therapeutic combinations that may lead to more durable responses. |
| Databáze: | OpenAIRE |
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