Dasatinib as a Network-modulating Tyrosine Kinase Inhibitor in Philadelphia Chromosome-positive Leukemias: Integration of BCR-ABL1, SRC, and MAPK Signaling
TL;DR
This review combines many forms of evidence, including mechanistic, phosphoproteomic, immunologic and clinical evidence, to show that dasatinib acts as a network-modulating tyrosine kinase inhibitor rather than only as an ABL1-directed agent.
Abstract
Philadelphia chromosome-positive leukemias involve signaling systems beyond BCR-ABL1, and treatment response may depend on this wider network biology. Second-generation BCR-ABL1 tyrosine kinase inhibitors such as dasatinib, nilotinib, and bosutinib show variable clinical responses according to diagnosis and disease stage. Dasatinib is effective in this context because it is active against SRC-family kinases as well as receptor-proximal kinases and downstream outputs involving the MAPK/ERK, PI3K/AKT and JAK/STAT pathways. This broader pharmacological profile may impair compensatory signaling, which may partly account for its activity against CML and Philadelphia chromosome-positive ALL, especially if SRC-linked or ERK-mediated persistence underlies treatment escape. However, the same breadth could trigger pleural effusion and immune-related effects, underscoring the need for personalized dosing, toxicity monitoring, and adaptive interpretation of responses. This review combines many forms of evidence, including mechanistic, phosphoproteomic, immunologic and clinical evidence, to show that dasatinib acts as a network-modulating tyrosine kinase inhibitor rather than only as an ABL1-directed agent. Translational biomarkers, host immune responses, and systems-biology strategies may help predict incomplete pathway inhibition, guide treatment selection, and improve the durability of deep molecular remission.