Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a malignant clonal disease involving hematopoietic stem cells that is characterized by myeloid cell proliferation in bone marrow and peripheral blood, and the presence of the Philadelphia (Ph) chromosome with BCR-ABL fusion gene. Treatment of CML has dramatically improved since the advent of tyrosine kinase inhibitors (TKI). However, there are a small subset of CML patients who develop resistance to TKI. Mutations in the ABL kinase domain (KD) are currently recognized as the leading cause of TKI resistance in CML. In this review, we discuss the concept of resistance and summarize recent advances exploring the mechanisms underlying CML resistance. Overcoming TKI resistance appears to be the most successful approach to reduce the burden of leukemia and enhance cures for CML. Advances in new strategies to combat drug resistance may rapidly change the management of TKI-resistant CML and expand the prospects for available therapies.

Lycorine attenuated proliferation and induced apoptosis on imatinib-resistant K562 cell by inhibiting autophagy

“…While TKIs have demonstrated efficacy in a substantial proportion of CML patients, there exists a need for further exploration and refinement of treatment modalities to address potential limitations and enhance overall patient outcomes [ 15 ], a significant proportion of individuals still harbor residual leukemia cells during prolonged medical treatment, with relapse anticipated upon discontinuation of TKI therapy [ 16 ]. Among these patients, about 20–30% may develop acquired resistance to long-term TKI administration [ 17 ]. The emergence of resistance, particularly in the case of TKIs like IM, significantly hampers their efficacy in the management of CML patients.…”