Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors

Chronic myeloid leukemia is increasingly viewed as a chronic illness; most patients have a life expectancy close to that of the general population. Despite progress made using BCR-ABL1 tyrosine kinase inhibitors (TKIs), drug resistance via BCR-ABL1–dependent and BCR-ABL1–independent mechanisms continues to be an issue. BCR-ABL1–dependent resistance is primarily mediated through oncoprotein kinase domain mutations and usually results in overt resistance to TKIs. However, BCR-ABL1–independent resistance in the setting of effective BCR-ABL1 inhibition is recognized as a major contributor to minimal residual disease. Efforts to eradicate persistent leukemic stem cells have focused on combination therapy.

Key points

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More than 25% of patients with chronic myeloid leukemia (CML) will switch tyrosine kinase inhibitors (TKIs) during their lifetime owing to resistance or intolerance.
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Ponatinib is the only TKI effective against the T315I BCR-ABL1 mutation; its activity derives from its lack of dependence on forming a critical hydrogen bond with residue T315 for high-affinity binding to BCR-ABL1.
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Diverse pathways involving growth factors, epigenetic regulators, and apoptotic machinery have been implicated in BCR-ABL1–independent resistance.
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CML leukemic stem cells are resistant to TKI therapy and contribute to minimal residual disease. Combination strategies using TKIs and other drugs are an intense focus of investigation.
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A minority of patients with CML who achieve sustained deep molecular responses on TKI therapy are able to discontinue treatment without molecular recurrence, entering a state called “treatment-free remission.”