Targeted therapy in acute myeloid leukemia: Resistance and overcoming strategy

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid blasts, leading to hematopoietic suppression and bone marrow failure. Advances in understanding the pathogenesis of AML have fueled the development of precision medicine approaches, with notable successes in targeting specific mutant proteins (e.g., FLT3, IDH1, IDH2), apoptotic regulators (e.g., BCL-2, MCL1), and cell-surface antigens (e.g., CD33, CD123, CD47). These targeted inhibitors exhibit moderate antileukemic activity as monotherapies and their clinical responses are often limited due to the emergence of drug resistance and disease relapse. Nevertheless, synergistic effects have been observed when these agents are combined with conventional chemotherapy or oncogenic pathway inhibitors. This review analyzes the current limitations of targeted therapies and explores multifaceted resistance drivers, encompassing on-target mutations, compensatory signaling pathway activation, drug-efflux mechanisms mediated by metabolic enzymes or transporters, intrinsic adaptive changes, and interactions with the tumor microenvironment. Corresponding therapeutic counterstrategies are also examined, such as mutation-specific molecular targeting, combinatorial suppression of alternative pathways, disruption of intrinsic adaptive responses, and immunotherapeutic approaches. These evolving interventions aim to overcome specific resistance mechanisms and reduce relapse rates. Future research integrating these strategies holds significant promise for addressing persistent challenges in AML management, ultimately advancing treatment paradigms and patient survival.