Molecular Mechanisms of Resistance to Tyrosine Kinase Inhibitors.

Abstract

Chronic myeloid leukemia (CML) patients with constitutive activity of BCR-ABL1 oncoprotein frequently derive significant clinical benefits from tyrosine kinase inhibitors (TKIs). Point mutations in the ABL1 kinase domain (KD) are an important mechanism of TKI resistance in CML. In this review, we present molecular mechanisms of TKI resistance paying particular attention to drug resistance which allows for a survival advantage in CML. Sensitive disease monitoring is a required standard of care for management of CML. Screening of these mutations fail to explain 20-40% of resistant cases where activation of different survival pathways must be the main reason for resistance. Eliminating TKI resistance appears to be the most successful therapeutic way to decrease leukemic disease burden and potentiate cure. Advances on novel strategies for identifying and confronting drug resistance are rapidly altering management of CML that are resistant to TKI and expanding the landscape of available therapies.