Mechanistic overview and suggested strategies to overcome BCL-2 inhibitor resistance in mutated acute myeloid leukemia.

Venetoclax is a selective BCL-2 inhibitor that has transformed the treatment landscape for elderly and unfit patients with acute myeloid leukemia (AML). Its use has also been progressively extended to include -mutated AML based on clinical outcomes comparable to other available standards of care. However, -mutated AML is associated with high rates of primary and acquired resistances to venetoclax combinations, which have not afforded any meaningful gains to overall survival. The main causes for these limitations include profound genomic instability, loss of p53 pleotropic function, an immunosuppressive and exhausted marrow microenvironment, a shift away from BCL-2 dependence, defects in the post-mitochondrial executioner phase of apoptosis, lineage plasticity and monocytic differentiation, upregulation of fatty acid metabolism, and BCL-2 family gene mutations. In the present review, we discuss the pathobiology of the BCL-2 family of proteins in -mutated AML, mechanisms of venetoclax/BCL-2 inhibitor resistance in this molecular subset, and emerging strategies to potentially overcome this deficiency to guide therapeutic management for a population of patients who are in critical need of progress.