Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance

Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of BCR::ABL1 are the most extensively studied mechanism of TKI resistance in CML, but BCR::AB...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-09, Vol.24 (18), p.13806
Main Authors: Yoshimaru, Ryo, Minami, Yosuke
Format: Article
Language:English
Subjects:
Analysis
asciminib
Cancer
Chromosomes
Chronic myeloid leukemia
Clinical trials
Development and progression
DNA damage
Drug resistance
Gene amplification
Gene mutations
Genes
Genetic aspects
Genetic research
genome profiling
Kinases
Leukemia
Medical prognosis
Mutation
Nilotinib
Phosphorylation
Remission (Medicine)
Review
Tyrosine
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Summary:Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of BCR::ABL1 are the most extensively studied mechanism of TKI resistance in CML, but BCR::ABL1-independent mechanisms are involved in some cases. There are two known types of mechanisms that contribute to resistance: mutations in known cancer-related genes; and Philadelphia-associated rearrangements, a novel mechanism of genomic heterogeneity that occurs at the time of the Philadelphia chromosome formation. Most chronic-phase and accelerated-phase CML patients who were treated with the third-generation TKI for drug resistance harbored one or more cancer gene mutations. Cancer gene mutations and additional chromosomal abnormalities were found to be independently associated with progression-free survival. The novel agent asciminib specifically inhibits the ABL myristoyl pocket (STAMP) and shows better efficacy and less toxicity than other TKIs due to its high target specificity. In the future, pooled analyses of various studies should address whether additional genetic analyses could guide risk-adapted therapy and lead to a final cure for CML.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241813806