mTORC1/autophagy-regulated MerTK in mutant BRAFV600 melanoma with acquired resistance to BRAF inhibition.

// Gongda Xue 1 , Reto Kohler 1 , Fengyuan Tang 1,2 , Debby Hynx 1 , Yuhua Wang 1 , Francesca Orso 3 , Vincent Pretre 2 , Reto Ritschard 2 , Petra Hirschmann 4 , Peter Cron 1 , Tim Roloff 1 , Reinhard Dummer 5 , Mario Mandala 6 , Sandrine Bichet 1 , Christel Genoud 1 , Alexandra G. Meyer 1 , Manuele G. Muraro 2 , Giulio C. Spagnoli 2 , Daniela Taverna 3 , Curzio Ruegg 7 , Taha Merghoub 8 , Daniela Massi 9 , Huifang Tang 10 , Mitchell P. Levesque 5 , Stephan Dirnhofer 4 , Alfred Zippelius 2 , Brian A. Hemmings 1 and Andreas Wicki 2 1 Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland 2 Department of Biomedicine, University Hospital Basel, Basel, Switzerland 3 Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy 4 Institute of Pathology, University of Basel, Basel, Switzerland 5 Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland 6 Unit of Clinical and Translational Research, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy 7 Department of Medicine, University of Fribourg, Fribourg, Switzerland 8 Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 9 Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy 10 Department of Pharmacology, Zhejiang University, School of Basic Medical Sciences, Hangzhou, China Correspondence to: Gongda Xue, email: // Keywords : Mer tyrosine kinase, drug resistance, BRAF mutation, Zeb2, autophagy Received : May 09, 2017 Accepted : May 17, 2017 Published : May 25, 2017 Abstract 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.