Patients with advanced
systemic mastocytosis, including
mast cell leukemia, have a poor prognosis. In these patients, neoplastic mast cells usually harbor the KIT mutant D816V that confers resistance against
tyrosine kinase inhibitors. We examined the effects of the multi-
kinase blocker
ponatinib on neoplastic mast cells and investigated whether
ponatinib acts synergistically with other
antineoplastic drugs.
Ponatinib was found to inhibit the
kinase activity of KIT G560V and KIT D816V in the human
mast cell leukemia cell line HMC-1. In addition,
ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells.
Ponatinib induced growth inhibition and apoptosis in HMC-1.1 cells (KIT G560V(+)) and HMC-1.2 cells (KIT G560V(+)/KIT D816V(+)) as well as in primary neoplastic mast cells. The effects of
ponatinib were dose-dependent, but higher IC50-values were obtained in HMC-1 cells harboring KIT D816V than in those lacking KIT D816V. In
drug combination experiments,
ponatinib was found to synergize with
midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk
short interfering RNA and found that Btk knockdown sensitizes HMC-1 cells against
ponatinib. Finally, we were able to show that
ponatinib synergizes with the Btk-targeting
drug dasatinib to produce growth inhibition in HMC-1 cells. In conclusion,
ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced
systemic mastocytosis and synergizes with
midostaurin and
dasatinib in inducing growth arrest in neoplastic mast cells.