Mechanisms of Resistance to Small Molecules in Acute Myeloid Leukemia

SIMPLE SUMMARY: Acute myeloid leukemia (AML) is a dangerous cancer of the blood. In recent years, a series of drugs was approved to specifically target misdirected processes in the cancerous cells. These so-called “small molecules” substantially improved therapeutic outcomes, but eventually leukemia returns in most patients. In this review, we summarize the current state of knowledge regarding the mechanisms that lead to failure of the most frequently used new therapies and introduce potential strategies to overcome the mechanisms associated with disease recurrence. ABSTRACT: In recent years, great progress has been made in the therapy of AML by targeting cellular processes associated with specific molecular features of the disease. Various small molecules inhibiting FLT3, IDH1/IDH2, and BCL2 have already gained approval from the respective authorities and are essential parts of personalized therapeutic regimens in modern therapy of AML. Unfortunately, primary and secondary resistance to these inhibitors is a frequent problem. Here, we comprehensively review the current state of knowledge regarding molecular processes involved in primary and secondary resistance to these agents, covering both genetic and nongenetic mechanisms. In addition, we introduce concepts and strategies for how these resistance mechanisms might be overcome.