Contributions
Abstract: EP1070
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Biology & Translational Research
Background
Systemic mastocytosis (SM) is a hematopoietic neoplasm defined by abnormal growth and accumulation of neoplastic mast cells (MC) in various internal organs. Major drivers of SM are activating mutations in KIT, especially the D816V point mutation, which initiates ligand-independent signaling in MC.
Aims
Several tyrosine kinase inhibitors targeting KIT have already shown clinical activity. However, the D816V KIT mutation confers resistance against most KIT-targeting drugs.
Methods
We evaluated the effects of two novel KIT D816V-targeting drugs, avapritinib and nintedanib, on growth and function of neoplastic MC and compared their activity profiles with that of midostaurin.
Results
Avapritinib was found to suppress growth of HMC-1.1 (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 block proliferation of ROSAKIT WT (IC50: 0.1-0.25 µM), ROSAKIT D816V (IC50: 1-5 µM), and ROSAKIT K509I cells (IC50: 0.1-0.25 µM). Even stronger effects were seen with nintedanib (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: 1-5 µM; ROSAKIT K509I: 0.001-0.01 µM). Avapritinib and nintedanib also suppressed the growth of primary neoplastic MC in most patients with advanced SM (IC50 of avapritinib: 1-5 µM; IC50 of nintedanib: 0.1-5 µM). Growth-inhibitory drug effects were accompanied by signs of apoptosis and downregulation of activation-linked surface antigens CD63, CD71 and CD117 (KIT) in MC. Contrasting midostaurin, both drugs failed to inhibit IgE-dependent histamine release in MC or basophils.
Conclusion
Contrasting midostaurin, both drugs failed to inhibit IgE-dependent histamine release in MC or basophils. In conclusion, our data suggest that avapritinib and nintedanib are promising drugs for treatment of patients with advanced SM.
Keyword(s): Mast cell, Mastocytosis, Targeted therapy, Tyrosine kinase inhibitor
Abstract: EP1070
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Biology & Translational Research
Background
Systemic mastocytosis (SM) is a hematopoietic neoplasm defined by abnormal growth and accumulation of neoplastic mast cells (MC) in various internal organs. Major drivers of SM are activating mutations in KIT, especially the D816V point mutation, which initiates ligand-independent signaling in MC.
Aims
Several tyrosine kinase inhibitors targeting KIT have already shown clinical activity. However, the D816V KIT mutation confers resistance against most KIT-targeting drugs.
Methods
We evaluated the effects of two novel KIT D816V-targeting drugs, avapritinib and nintedanib, on growth and function of neoplastic MC and compared their activity profiles with that of midostaurin.
Results
Avapritinib was found to suppress growth of HMC-1.1 (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 block proliferation of ROSAKIT WT (IC50: 0.1-0.25 µM), ROSAKIT D816V (IC50: 1-5 µM), and ROSAKIT K509I cells (IC50: 0.1-0.25 µM). Even stronger effects were seen with nintedanib (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: 1-5 µM; ROSAKIT K509I: 0.001-0.01 µM). Avapritinib and nintedanib also suppressed the growth of primary neoplastic MC in most patients with advanced SM (IC50 of avapritinib: 1-5 µM; IC50 of nintedanib: 0.1-5 µM). Growth-inhibitory drug effects were accompanied by signs of apoptosis and downregulation of activation-linked surface antigens CD63, CD71 and CD117 (KIT) in MC. Contrasting midostaurin, both drugs failed to inhibit IgE-dependent histamine release in MC or basophils.
Conclusion
Contrasting midostaurin, both drugs failed to inhibit IgE-dependent histamine release in MC or basophils. In conclusion, our data suggest that avapritinib and nintedanib are promising drugs for treatment of patients with advanced SM.
Keyword(s): Mast cell, Mastocytosis, Targeted therapy, Tyrosine kinase inhibitor