Mechanism of Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukaemia: Signalling Pathway Crosstalk and Therapeutic Strategies

Tyrosine kinase inhibitors (TKIs) have transformed chronic myeloid leukaemia (CML) from a fatal disease into a manageable chronic condition by targeting the BCR-ABL1 oncoprotein. However, primary and acquired resistance continue to compromise long-term outcomes. This review examines the molecular basis of TKI resistance, encompassing BCR-ABL1-dependent mechanisms such as kinase domain mutations and gene amplification, alongside BCR-ABL1-independent pathways including PI3K/AKT, RAS/MAPK, and JAK/STAT5 crosstalk, drug transporters, epigenetic changes, and leukemic stem cell persistence. Emerging therapeutic strategies—allosteric inhibitors, rational combinations, stem-cell-directed approaches, and novel degrader technologies—are discussed as promising avenues toward overcoming resistance and achieving durable, treatment-free remission.