# Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies

## TL;DR

This paper reviews why targeted therapies for AML often fail and explores new strategies to overcome resistance.

## Contribution

The paper provides a comprehensive overview of resistance mechanisms and novel treatment approaches in AML targeted therapy.

## Key findings

- Resistance mechanisms include mutations, genetic alterations, and metabolic changes.
- Combination therapies and novel inhibitors are proposed to overcome resistance.
- Clonal heterogeneity and the bone marrow microenvironment contribute to resistance.

## Abstract

The development of targeted treatments, including inhibitors of BCL-2, FLT3, IDH1/2, and menin, has significantly expanded the therapeutic landscape of acute myeloid leukemia (AML), offering more personalized and molecularly driven treatment approaches. Despite these advances, achieving durable responses represents a major challenge, limited by the emergence of intrinsic and acquired resistance to targeted agents. This review summarizes the current understanding of the cellular and molecular mechanisms underlying resistance to targeted therapies in AML. Key mechanisms include acquired mutations that alter the drug target, other co-occurring genetic and epigenetic alterations, activation of bypass signaling pathways, and metabolic reprogramming. Furthermore, the role of clonal heterogeneity and the bone marrow microenvironment in the development of resistance is increasingly recognized. In addition, we discuss emerging strategies aiming at overcoming resistance, such as combination treatments and novel inhibitors designed to target resistant clones. Finally, this review highlights the critical need for mechanism-driven therapeutic design in order to achieve sustained responses and improve long-term outcomes in patients with AML.