Muralidharan Somsundar Veppil, Einarsdottir Berglind Osk, Bhadury Joydeep, Lindberg Mattias F, Wu Jin, Campeau Eric, Bagge Roger Olofsson, Stierner Ulrika, Ny Lars, Nilsson Lisa M, Nilsson Jonas A
Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden.
The Institute of Medical Science, Division of Stem Cell Therapy, The University of Tokyo, Tokyo, Japan.
Cell Death Dis. 2017 Aug 10;8(8):e2982. doi: 10.1038/cddis.2017.383.
Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.
尽管对驱动突变以及黑色素瘤细胞如何逃避免疫攻击有了全面的临床认识，但转移性恶性黑色素瘤仍然是一种具有挑战性的疾病。在Myc驱动的淋巴瘤中，通过与DNA损伤反应激酶ATR抑制剂联合治疗，可以增强溴结构域和额外末端结构域（BET）家族溴结构域蛋白的表观遗传抑制剂的疗效。这种联合疗法在黑色素瘤等实体恶性肿瘤中是否有效，以及它与免疫治疗的关系，此前尚未得到研究。为了测试联合疗法的疗效和分子后果，我们使用了培养的黑色素瘤细胞。为了评估体内疗法对肿瘤的反应，我们使用了患者来源的异种移植模型以及移植了B16F10黑色素瘤细胞的B6小鼠。对培养的黑色素瘤细胞同时抑制BET蛋白和ATR，产生了与最近在淋巴瘤中所显示的类似效果，如诱导凋亡和自噬、衰老相关分泌途径及内质网应激中涉及的p62。在体内，观察到了患者来源的黑色素瘤和B16F10细胞的凋亡以及皮下生长受到抑制。我们的数据表明，ATR抑制剂/ BET抑制剂联合疗法在黑色素瘤中是有效的。
