Therapy Resistance and Disease Progression in CML: Mechanistic Links and Therapeutic Strategies

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Tyrosine kinase inhibitors (TKIs) are standard molecular targeted therapy for chronic myeloid leukemia (CML).
• Despite TKI efficacy, a subset of patients exhibit primary resistance or develop secondary resistance, leading to disease progression.
• Understanding resistance mechanisms is crucial for improving CML treatment outcomes.

Purpose of the Study:

• To review advances in understanding the mechanisms of TKI resistance in CML.
• To summarize management strategies for overcoming or preventing drug resistance.
• To highlight the importance of leukemia stem cells (LSCs) in achieving a cure for CML.

Main Methods:

• Literature review of studies on TKI resistance in chronic myeloid leukemia.
• Analysis of mechanisms including BCR-ABL1 mutations, cell-intrinsic factors, and extrinsic pathways.
• Examination of therapeutic strategies targeting resistance.

Main Results:

• TKI resistance arises from diverse mechanisms, including BCR-ABL1 mutations and inherent resistance of primitive stem cells.
• Leukemia stem cells (LSCs) possess intrinsic resistance and contribute to CML persistence.
• Heterogeneity in TKI response among hematopoietic populations influences treatment outcomes.
• Targeting BCR-ABL1 kinase alone may not be sufficient for CML cure.

Conclusions:

• BCR-ABL1-independent mechanisms and LSC persistence are critical challenges in CML therapy.
• Future strategies must address these resistance pathways to improve cure rates.
• A comprehensive understanding of LSCs is essential for eradicating CML.