Antineoplastic efficacy profiles of avapritinib and nintedanib in KIT D816V+systemic mastocytosis: a preclinical study

被引:0
作者
Degenfeld-Schonburg, Lina [1 ]
Gamperl, Susanne [1 ]
Stefanzl, Gabriele [1 ,2 ]
Schruef, Anna-Katharina [1 ]
Sadovnik, Irina [2 ]
Bauer, Karin [2 ]
Smiljkovic, Dubravka [2 ]
Eisenwort, Gregor [1 ,2 ]
Peter, Barbara [1 ,2 ]
Greiner, Georg [2 ,3 ]
Hadzijusufovic, Emir [1 ,2 ,4 ]
Schwaab, Juliana [5 ,6 ]
Sperr, Wolfgang R. [1 ,2 ]
Hoermann, Gregor [2 ,7 ]
Kopanja, Sonja [8 ]
Szepfalusi, Zsolt [8 ]
Hoetzenecker, Konrad [9 ]
Jaksch, Peter [9 ]
Reiter, Andreas [5 ,6 ]
Arock, Michel [10 ]
Valent, Peter [1 ,2 ]
机构
[1] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Vienna, Austria
[2] Med Univ Vienna, Ludwig Boltzmann Inst Hematol & Oncol, Vienna, Austria
[3] Ihr Lab, Med Diagnost Labs, Vienna, Austria
[4] Univ Vet Med Vienna, Univ Hosp Small Anim, Dept Hosp Compan Anim & Horses, Internal Med Small Anim, Vienna, Austria
[5] Heidelberg Univ, Univ Med Ctr Mannheim, Dept Hematol & Oncol, Mannheim, Germany
[6] Heidelberg Univ, Med Fac Mannheim, Mannheim, Germany
[7] MLL Munich Leukemia Lab, Munich, Germany
[8] Med Univ Vienna, Dept Pediat & Adolescent Med, Div Pediat Pulmonol Allergy & Endocrinol, Vienna, Austria
[9] Med Univ Vienna, Dept Surg, Div Thorac Surg, Vienna, Austria
[10] Pierre & Marie Curie Univ UPMC, Pitie Salpetriere Hosp, Dept Hematol Biol, Paris, France
来源
AMERICAN JOURNAL OF CANCER RESEARCH | 2023年 / 13卷 / 02期
基金
奥地利科学基金会;
关键词
Mast cells; mastocytosis; KIT; tyrosine kinase inhibitors; targeted therapy; NEOPLASTIC MAST-CELLS; CURRENT TREATMENT OPTIONS; HUMAN-BLOOD BASOPHILS; PROTOONCOGENE C-KIT; SYSTEMIC MASTOCYTOSIS; ACTIVATION; CLASSIFICATION; MIDOSTAURIN; CLADRIBINE; GROWTH;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 me-diators 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 pM). In addition, avapritinib was found to inhibit the prolifera-tion of ROSA(KIT WT) cells, (IC50: 0.1-0.25 pM), ROSA(KIT D816V) cells (IC50: 1-5 pM), and ROSA(KIT K509I) cells (IC50: 0.1-0.25 pM). Nintedanib exerted even stronger growth-inhibitory effects in these cells (IC50 in HMC-1.1: 0.001-0.01 pM; HMC-1.2: 0.25-0.5 pM; ROSA(KIT WT): 0.01-0.1 pM; ROSA(KIT D816V): 0.5-1 pM; ROSA(KITK509I): 0.01-0.1 pM). Avapritinib and nintedanib also suppressed the growth of primary neoplastic cells in most patients with SM examined (avapritinib IC50: 0.5-5 pM; nintedanib IC50: 0.1-5 pM). 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 sur-vival 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.
引用
收藏
页码:355 / 378
页数:24
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