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Abstract：
Systemic mastocytosis (SM) is a hematopoietic neoplasm with a complex pathology and a variable clinical course. Clinical symptoms result from organ infiltration by mast cells (MC) and the effects of pro-inflammatory mediators released during MC activation. In SM, growth and survival of MC are triggered by various oncogenic mutant-forms of the tyrosine kinase KIT. The most prevalent variant, D816V, confers resistance against various KIT-targeting drugs, including imatinib. We examined the effects of two novel promising KIT D816V-targeting drugs, avapritinib and nintedanib, on growth, survival, and activation of neoplastic MC and compared their activity profiles with that of midostaurin. Avapritinib was found to suppress growth of HMC-1.1 cells (KIT V560G) and HMC-1.2 cells (KIT V560G + KIT D816V) with comparable IC50 values (0.1-0.25 µM). In addition, avapritinib was found to inhibit the proliferation of ROSAKIT WT cells, (IC50: 0.1-0.25 µM), ROSAKIT D816V cells (IC50: 1-5 µM), and ROSAKIT K509I cells (IC50: 0.1-0.25 µM). Nintedanib exerted even stronger growth-inhibitory effects in these cells (IC50 in HMC-1.1: 0.001-0.01 µM; HMC-1.2: 0.25-0.5 µM; ROSAKIT WT: 0.01-0.1 µM; ROSAKIT D816V: 0.5-1 µM; ROSAKIT K509I: 0.01-0.1 µM). Avapritinib and nintedanib also suppressed the growth of primary neoplastic cells in most patients with SM examined (avapritinib IC50: 0.5-5 µM; nintedanib IC50: 0.1-5 µM). Growth-inhibitory effects of avapritinib and nintedanib were accompanied by signs of apoptosis and decreased surface expression of the transferrin receptor CD71 in neoplastic MC. Finally, we were able to show that avapritinib counteracts IgE-dependent histamine secretion in basophils and MC in patients with SM. These effects of avapritinib may explain the rapid clinical improvement seen during treatment with this KIT inhibitor in patients with SM. In conclusion, avapritinib and nintedanib are new potent inhibitors of growth and survival of neoplastic MC expressing various KIT mutant forms, including D816V, V560G, and K509I, which favors the clinical development and application of these new drugs in advanced SM. Avapritinib is of particular interest as it also blocks mediator secretion in neoplastic MC.
摘要：
系统性肥大细胞增多症（SM）是一种病理复杂，临床过程多变的造血肿瘤。临床症状由肥大细胞（MC）的器官浸润和MC激活过程中释放的促炎介质的作用引起。在SM中，MC的生长和存活是由酪氨酸激酶KIT的各种致癌突变形式触发的。最普遍的变种,D816V,赋予对各种KIT靶向药物的抵抗力，包括伊马替尼.我们检查了两种新型有前途的KITD816V靶向药物的作用，阿伐替尼和尼达尼,关于增长，生存,和肿瘤MC的激活，并将它们的活性谱与midostaurin的活性谱进行了比较。发现阿伐替尼抑制HMC-1.1细胞（KITV560G）和HMC-1.2细胞（KITV560G+KITD816V）的生长，IC50值相当（0.1-0.25µM）。此外,发现阿伐替尼抑制ROSAKITWT细胞的增殖，(IC50:0.1-0.25µM),ROSAKITD816V电池（IC50：1-5µM），和ROSAKITK509I细胞（IC50：0.1-0.25µM）。Nintedanib在这些细胞中具有更强的生长抑制作用（HMC-1.1中的IC50：0.001-0.01µM;HMC-1.2：0.25-0.5µM;ROSAKITWT：0.01-0.1µM;ROSAKITD816V：0.5-1µM;ROSAKITK509I：0.01-0.1µM）。在大多数接受SM检查的患者中，Avapritinib和nintedanib也抑制了原发性肿瘤细胞的生长（avapritinibIC50：0.5-5µM;nintedanibIC50：0.1-5µM）。阿伐替尼和尼达尼布的生长抑制作用伴随着细胞凋亡的迹象和肿瘤MC中转铁蛋白受体CD71的表面表达减少。最后,我们能够证明阿伐替尼能抵消SM患者嗜碱性粒细胞和MC中IgE依赖性组胺的分泌.阿伐替尼的这些作用可以解释在SM患者中使用这种KIT抑制剂治疗期间观察到的快速临床改善。总之,阿伐替尼和尼达尼是表达各种KIT突变形式的肿瘤MC生长和存活的新的有效抑制剂，包括D816V,V560G,和K509I,这有利于这些新药在高级SM中的临床开发和应用。阿瓦维替尼特别令人感兴趣,因为它还阻断肿瘤MC中的介质分泌。
