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

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2023 Nov 25

PMID 38004514

Authors

Noor E Verhagen

Jan B Koenderink

Nicole M A Blijlevens

Jeroen J W M Janssen

Frans G M Russel

Affiliations

Soon will be listed here.

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 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.

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