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REVIEW

Therapeutic Targets for Overcoming BCR::ABL1 Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia

Masanobu Tsubaki*, Taira Matsuo, Rie Komori
Laboratory of Pharmacotherapy, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 8-53 Hamanocho, Takamatsu, 760-8542, Kagawa, Japan
* Corresponding Author: Masanobu Tsubaki. Email: email
(This article belongs to the Special Issue: Molecular Targeting Therapy for Anticancer Treatment)

Oncology Research https://doi.org/10.32604/or.2025.075217

Received 27 October 2025; Accepted 26 December 2025; Published online 20 January 2026

Abstract

Chronic myeloid leukemia (CML) is a hematopoietic malignancy originating from hematopoietic stem cells. It is characterized by the Philadelphia chromosome, which arises from a reciprocal translocation between chromosomes 9 and 22. The breakpoint cluster region::Abelson murine leukemia 1 (BCR::ABL1) fusion protein produced from this chromosome is the main factor responsible for disease onset. Tyrosine kinase inhibitors (TKIs) have led to significant advances in CML treatment and contributed to improved patient survival rates. Nonetheless, a substantial number of patients develop resistance to TKIs, which remains a major challenge in CML therapy. Currently, two mechanisms are considered responsible for TKIs resistance in CML: BCR::ABL1-dependent resistance, involving mutations or overexpression of BCR::ABL1, and BCR::ABL1-independent resistance, which does not depend on BCR::ABL1. This review discusses the recent findings on the resistance mechanisms mediated by BCR::ABL1 mutations. It also focuses on bypass pathways, the B-cell/CLL lymphoma 2 family, tumor suppressor genes, microRNAs, and molecular chaperones as independent resistance mechanisms. Furthermore, the potential for combination therapies targeting these resistance mechanisms is discussed, anticipating further advances in research aimed at overcoming TKI resistance in CML.

Keywords

Chronic myeloid leukemia; tyrosine kinase inhibitor; resistance; breakpoint cluster region::Abelson murine leukemia 1

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