Mechanisms and signaling pathways of tyrosine kinase inhibitor resistance in chronic myeloid leukemia: A comprehensive review

Abstract

Chronic Myeloid Leukemia (CML) is characterized by aberrant BCR::ABL1 tyrosine kinase activity in hematopoietic stem cells. Although tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment, resistance remains a major clinical challenge. This review provides a comprehensive overview of CML, including its epidemiology, pathophysiology, diagnosis, and treatment, as outlined in the latest WHO consensus classification. Current treatment paradigms and the prospects for treatment-free remission (TFR) are also explored. The primary focus is on elucidating the molecular mechanisms of TKI resistance, emphasizing both well-known pathways such as PI3K/AKT, MAPK, JAK/STAT, and alternative pathways including SRC/AKT. This review stands out by integrating recent discoveries regarding genetic mutations within the BCR::ABL1 gene, alongside other molecular alterations contributing to resistance. By synthesizing this knowledge, it aims to guide clinical practitioners, investigators, and translational researchers in developing innovative strategies to overcome resistance and improve patient outcomes in CML.

Keywords: BCR::ABL1 Mutations; Chronic myeloid leukemia; Signaling pathways; TKI resistance; Tyrosine kinase inhibitors.

Fig. 1

Therapeutic pathway to achieving therapy-free remission in chronic myeloid leukemia.

Fig. 2

Pathways of tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Modified from [21] using Biorander software.