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