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Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies.
Christos Stafylidis1, Panagiotis T Diamantopoulos1
1Hematology Unit, First Department of Internal Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece.
Journal of Clinical Medicine
|March 28, 2026
Summary
Targeted therapies for acute myeloid leukemia (AML) show promise, but resistance remains a challenge. Understanding resistance mechanisms is key to developing new strategies for durable patient responses.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Targeted therapies like BCL-2, FLT3, IDH1/2, and menin inhibitors have advanced acute myeloid leukemia (AML) treatment.
- Despite progress, intrinsic and acquired resistance limit durable responses in AML patients.
Purpose of the Study:
- To review cellular and molecular mechanisms of resistance to targeted therapies in AML.
- To discuss emerging strategies for overcoming resistance and improving long-term outcomes.
Main Methods:
- Literature review of current understanding of resistance mechanisms.
- Analysis of genetic, epigenetic, signaling, and metabolic factors contributing to resistance.
- Exploration of clonal heterogeneity and bone marrow microenvironment roles.
Main Results:
- Key resistance mechanisms include target mutations, co-occurring alterations, bypass pathways, and metabolic reprogramming.
- Clonal heterogeneity and the bone marrow microenvironment significantly contribute to resistance development.
- Combination therapies and novel inhibitors targeting resistant clones are emerging strategies.
Conclusions:
- A deeper understanding of resistance mechanisms is crucial for AML treatment.
- Mechanism-driven therapeutic design is essential for achieving sustained responses and improving patient outcomes.
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