Xue Gongda, Kohler Reto, Tang Fengyuan, Hynx Debby, Wang Yuhua, Orso Francesca, Prêtre Vincent, Ritschard Reto, Hirschmann Petra, Cron Peter, Roloff Tim, Dummer Reinhard, Mandalà Mario, Bichet Sandrine, Genoud Christel, Meyer Alexandra G, Muraro Manuele G, Spagnoli Giulio C, Taverna Daniela, Rüegg Curzio, Merghoub Taha, Massi Daniela, Tang Huifang, Levesque Mitchell P, Dirnhofer Stephan, Zippelius Alfred, Hemmings Brian A, Wicki Andreas
Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Oncotarget. 2017 May 25;8(41):69204-69218. doi: 10.18632/oncotarget.18213. eCollection 2017 Sep 19.
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.
BRAF抑制剂（BRAFi）以及BRAF与MEK抑制剂（MEKi）的联合疗法最近被批准用于治疗携带致癌性BRAFV600突变的转移性黑色素瘤。尽管这些疗法已显示出显著的治疗效果，但反应的有限持久性表明存在获得性耐药，在分子水平上其机制仍知之甚少。我们对BRAFi处理的黑色素瘤细胞进行了转录组基因分析，并确定Mer酪氨酸激酶（MerTK）特异性上调。MerTK过表达不仅在对BRAFi单药治疗耐药的黑色素瘤中得到证实（来自黑色素瘤患者的10个样本中有5个），而且在对BRAFi+MEKi耐药的黑色素瘤中也得到证实（3个中有1个），尽管单独使用MEKi并不影响MerTK。从机制上讲，BRAFi诱导的Zeb2激活通过mTORC1触发的自噬激活在BRAFV600黑色素瘤中刺激MerTK。共同靶向MerTK和BRAFV600显著降低了异种移植小鼠的肿瘤负担，这通过自噬和突变型BRAFV600的共同抑制在表型上得以复制。
