New therapeutic strategies for overcoming resistance and disease persistence in CML

Abstract

Abstract The emergence of resistance to molecular target therapies such as ABL-tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has become a significant problem despite the remarkable clinical results. The most common cause of resistance is the selection of leukemic clones with point mutations in the kinase domain, and overexpression of target molecules is another reason of resistance. For overcoming the resistance, the new generation of ABL-TKIs such as ponatinib (the clinical study is going on to reveal the mechanisms of adverse effects based on the PK/PD/PGx), the novel anti-metabolic signal agents, and the allosteric inhibitors are under research & development. The concept of leukemia stem cells harmonized with genetic diversity also become critical in understanding the CML pathogenesis, and the candidates of molecular target in CML stem-like cells are expanding. The disease persistence considered with the anti-leukemia immunology is another therapeutic challenge. To develop modalities for the minimum residual disease (MRD) and rationale biomarkers is also an important issue in CML therapy.