mTORC1/autophagy-regulated MerTK in mutant BRAFV600 melanoma with acquired resistance to BRAF inhibition
| Autor: | Sandrine Bichet, Daniela Taverna, Fengyuan Tang, Curzio Rüegg, Debby Hynx, Alfred Zippelius, Reto S. Kohler, Alexandra Graff Meyer, Daniela Massi, Manuele G. Muraro, Taha Merghoub, Tim Roloff, Mitchell P. Levesque, Yuhua Wang, Christel Genoud, Francesca Orso, Petra Hirschmann, Huifang Tang, Stephan Dirnhofer, Brian A. Hemmings, Giulio C. Spagnoli, Vincent Prêtre, Andreas Wicki, Reinhard Dummer, Peter Cron, Mario Mandalà, Gongda Xue, Reto Ritschard |
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| Přispěvatelé: | University of Zurich, Xue, Gongda |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Veterinary medicine autophagy Combination therapy Autophagy BRAF mutation Drug resistance Mer tyrosine kinase Zeb2 Oncology 610 Medicine & health mTORC1 Transcriptome 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Medicine neoplasms drug resistance business.industry Melanoma 10177 Dermatology Clinic MERTK medicine.disease 3. Good health 030104 developmental biology 030220 oncology & carcinogenesis Cancer research 2730 Oncology business Tyrosine kinase Priority Research Paper |
| Zdroj: | Oncotarget |
| Popis: | BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated. MerTK overexpression was demonstrated not only in melanomas resistant to BRAFi monotherapy (5 out of 10 samples from melanoma patients) but also in melanoma resistant to BRAFi+MEKi (1 out of 3), although MEKi alone does not affect MerTK. Mechanistically, BRAFi-induced activation of Zeb2 stimulates MerTK in BRAFV600 melanoma through mTORC1-triggered activation of autophagy. Co-targeting MerTK and BRAFV600 significantly reduced tumour burden in xenografted mice, which was pheno-copied by co-inhibition of autophagy and mutant BRAFV600. |
| Databáze: | OpenAIRE |
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