BH3 Mimetics in AML Therapy: Death and Beyond?. (November 2020) - Cerella, Claudia
Abstract : B cell lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics are targeted therapeutic agents that allow response prediction and patient stratification. BH3 mimetics are prototypical activators of the mitochondrial death program in cancer. They emerged as important modulators of cellular mechanisms contributing to poor therapeutic responses, including cancer cell stemness, cancer-specific metabolic routes, paracrine signaling to the tumor microenvironment, and immune modulation. We present an overview of the antagonism between BH3 mimetics and antiapoptotic BCL2 proteins. We focus on acute myeloid leukemia (AML), a cancer with reduced therapeutic options that have recently been improved by BH3 mimetics. Highlights: Acute myeloid leukemia (AML) is efficiently targeted by combinatorial regimens including B cell lymphoma 2 (BCL2) protein antagonists. BCL2 homology domain 3 (BH3) mimetics selectively target leukemic stem cells. Strategies that inhibit BCL2 proteins impair metabolic routes that are preferentially exploited in AML. BCL2 protein antagonists prevent BCL2 family member-dependent paracrine signaling to the AML tumor microenvironment. Inhibition of MCL1 expression/activity modulates the antitumor immune response.