Mechanisms of Resistance to Targeted Therapies in AML

Abstract

The treatment of acute myeloid leukemia (AML) has historically relied on cytotoxic chemotherapy, but modern understanding of AML biology has paved the way for new treatments that target the molecular pathways that drive AML, in particular FLT3, IDH1/IDH2, and BCL2. Many of these targeted therapies are effective, but responses are typically short-lived and resistance remains a ubiquitous clinical problem. Understanding the mechanisms of resistance to targeted therapy is essential to continue improving AML therapy. Recent studies have shed new light on the ways in which AML evades targeted inhibition, including on-target resistance mutations, mutations in parallel molecular pathways, and plasticity in cellular state. In this review, we outline the mechanisms of resistance to commonly used targeted therapies in AML and discuss ideas to overcome the urgent problem of resistance.