Capitalizing on paradoxical activation of the mitogen‐activated protein kinase pathway for treatment of Imatinib‐resistant mast cell leukemia

• DOI: 10.1002/hon.3100
• Publication Date: 2022-11-16T15:19:45Z
• Authors: Thomas Wilhelm; Marcelo A. S. Toledo; Ilka Simons; Christian Stuth; Vrinda Mohta; Ronja Mülfarth; Marcus Nitsche; Karin Maschke‐Neuß; Susanne Schmitz; Anne Kaiser; Jens Panse; Deborah Christen; Michel Arock; Martin Zenke; Michael Huber
• Keywords: Ponatinib; Trametinib

Prevention of fatal side effects during cancer therapy patients with high-dosed pharmacological inhibitors is to date a major challenge. Moreover, the development drug resistance poses severe problems for treatment leukemia or solid tumors. Particularly drug-mediated dimerization RAF kinases can be cause acquired resistance, also called "paradoxical activation." In present work we re-analyzed different tyrosine kinase (TKIs) on proliferation, metabolic activity, and survival Imatinib-resistant, KIT V560G, D816V-expressing human mast cell (MC) (MCL) line HMC-1.2. We observed that low concentrations TKIs Nilotinib Ponatinib resulted in enhanced suggesting paradoxical activation MAPK pathway. Indeed, these caused BRAF-CRAF dimerization, resulting ERK1/2 activation. The combination MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 induced apoptotic death. Effectiveness this was recapitulated D816V MC ROSAKIT hematopoietic progenitors obtained from patient-derived pluripotent stem cells (iPS cells) systemic mastocytosis patient samples. conclusion, mutated KIT-driven Imatinib possible TKI-induced efficiently overcome by concentration Trametinib co-treatment, potentially reducing negative associated MCL therapy.