Venetoclax resistance and molecular abnormalities in AML

Abstract

Venetoclax, a BCL-2 inhibitor, has transformed the treatment of elderly patients with acute myeloid leukemia (AML), but resistance remains a major clinical challenge. Approximately 30% of patients exhibit primary resistance, and many relapse despite achieving remission. Resistance mechanisms are multifaceted. AML stem cells rely on oxidative phosphorylation (OXPHOS) for survival, and venetoclax disrupts this energy metabolism by inducing mitochondrial dysfunction. However, resistant cells activate compensatory pathways such as fatty acid oxidation, amino acid metabolism, and the MEK-ERK signaling axis. Expression of anti-apoptotic proteins such as MCL-1 and BCL-XL also increases, circumventing BCL-2 inhibition. Furthermore, rare BCL2 mutations can directly impair drug binding. Sensitivity or resistance to venetoclax correlates strongly with specific molecular abnormalities. TP53 mutations predict poor response and survival, while RAS and FLT3 mutations confer moderate resistance. In contrast, IDH1/2 and NPM1 mutations are associated with high treatment sensitivity. Moving forward, personalized treatment strategies based on genetic profiles, along with combination therapies targeting metabolism or anti-apoptotic escape pathways, hold promise in overcoming resistance and improving outcomes in AML.