Hegedüs Luca, Okumus Özlem, Livingstone Elisabeth, Baranyi Marcell, Kovács Ildikó, Döme Balázs, Tóvári József, Bánkfalvi Ágnes, Schadendorf Dirk, Aigner Clemens, Hegedüs Balázs
Department of Thoracic Surgery, University Medicine Essen-Ruhrlandklinik, Tüschener Weg 40, 45239 Essen, Germany.
Department of Dermatology, University Medicine Essen, Esmarchstraße 14, 45147 Essen, Germany.
Cancers (Basel). 2021 Feb 16;13(4):829. doi: 10.3390/cancers13040829.
Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib-but not selumentinib-and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.
梭形细胞黑色素瘤是一种罕见的恶性肿瘤，其组织学特征与梭形痣相似。它具有多样的遗传背景，在成人中，临床结局与传统恶性黑色素瘤同样严峻。我们从一名37岁男性患者的胸腔积液样本中建立了一株梭形细胞黑色素瘤细胞系（PF130）。我们发现该细胞系携带一种罕见的MEK1突变（pGlu102_Lys104delinsGln），属于MEK1变异的RAF非依赖和磷酸化非依赖亚组，推测对变构MEK抑制剂不敏感。通过将细胞皮下、静脉注射或注入SCID小鼠的胸腔，在三种不同模型中测试了其体内致瘤性。在胸腔内模型中，两个月后胸腔内形成了肉眼可见的肿瘤，而皮下和静脉注射的细胞生长有限。在体外，曲美替尼而非塞鲁替尼以及ATP竞争性MEK抑制剂MAP855强烈降低了细胞活力并诱导细胞死亡。在体内，曲美替尼而非MAP855在胸腔内模型中显著降低了肿瘤生长。据我们所知，这是首个具有RAF非依赖和磷酸化非依赖MEK突变的患者来源黑色素瘤模型，并且我们证明了其对曲美替尼的敏感性。
