Oncotarget

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

Gongda Xue _, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G. Meyer, Manuele G. Muraro, Giulio C. Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P. Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A. Hemmings and Andreas Wicki

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Oncotarget. 2017; 8:69204-69218. https://doi.org/10.18632/oncotarget.18213

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Abstract

Gongda Xue1, Reto Kohler1, Fengyuan Tang1,2, Debby Hynx1, Yuhua Wang1, Francesca Orso3, Vincent Prêtre2, Reto Ritschard2, Petra Hirschmann4, Peter Cron1, Tim Roloff1, Reinhard Dummer5, Mario Mandalà6, Sandrine Bichet1, Christel Genoud1, Alexandra G. Meyer1, Manuele G. Muraro2, Giulio C. Spagnoli2, Daniela Taverna3, Curzio Rüegg7, Taha Merghoub8, Daniela Massi9, Huifang Tang10, Mitchell P. Levesque5, Stephan Dirnhofer4, Alfred Zippelius2, Brian A. Hemmings1 and Andreas Wicki2

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.


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