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Herein, we provide a comprehensive overview on the therapeutic strategies for overcoming acquired resistance to tyrosine kinase inhibitors (TKIs) targeting the most well-established oncogenic gene fusions in advanced NSCLC, including ALK, ROS1, RET, and NTRK rearrangements.Targeted therapy has become the standard of care for non-small cell lung cancers with a range of targetable alterations, including ALK and ROS1 kinase fusions. RET fusions drive the oncogenesis of 1-2% of NSCLCs and represent a substantial global burden of disease. Al