Transporter-Mediated Cellular Distribution of Tyrosine Kinase Inhibitors as a Potential Resistance Mechanism in Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a hematologic neoplasm characterized by the expression of the BCR::ABL1 oncoprotein, a constitutively active tyrosine kinase, resulting in uncontrolled growth and proliferation of cells in the myeloid lineage. Targeted therapy using tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib has drastically improved the life expectancy of CML patients. However, treatment resistance occurs in 10-20% of CML patients, which is a multifactorial problem that is only partially clarified by the presence of TKI inactivating BCR::ABL1 mutations. It may also be a consequence of a reduction in cytosolic TKI concentrations in the target cells due to transporter-mediated cellular distribution. This review focuses on drug-transporting proteins in stem cells and progenitor cells involved in the distribution of TKIs approved for the treatment of CML. Special attention will be given to ATP-binding cassette transporters expressed in lysosomes, which may facilitate the extracytosolic sequestration of these compounds.

Keywords: ABC transporters; cellular distribution; chronic myeloid leukemia; drug transporting proteins; treatment resistance; tyrosine kinase inhibitor.

Figure 1

TKIs currently approved for CML treatment.

Figure 2

Overview of the currently available data on transporter-mediated distribution of TKIs in leukemic stem cells discussed in this review; (A) cellular TKI uptake; (B) transporter-mediated TKI efflux; (C) inhibition of transporter activity by TKIs; (D) lysosomal expression of drug transporters and their impact on TKI transport.