Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia

Abstract

Acute myeloid leukaemia (AML) is a highly aggressive and devastating malignancy of the bone marrow and blood. For decades, intensive chemotherapy has been the frontline treatment for AML but has yielded only poor patient outcomes as exemplified by a 5-year survival rate of < 30%, even in younger adults. As knowledge of the molecular underpinnings of AML has advanced, so too has the development new strategies with potential to improve the treatment of AML patients. To date the most promising of these targeted agents is the BH3-mimetic venetoclax which in combination with standard of care therapies, has manageable non-haematological toxicity and exhibits impressive efficacy. However, approximately 30% of AML patients fail to respond to venetoclax-based regimens and almost all treatment responders eventually relapse. Here, we review the emerging mechanisms of intrinsic and acquired venetoclax resistance in AML and highlight recent efforts to identify novel strategies to overcome resistance to venetoclax.

Fig. 1. Overview of extrinsic and intrinsic regulation of apoptosis.

The extrinsic apoptosis pathway (left) is activated by ligand binding to either the FAS receptor (FASR), TRAIL receptors (TRAILR) or TNF receptor (TNFR) 1 or 2. This results in recruitment of the FAS associated death domain (FADD) that activates caspase 8 which in turn activates caspases 3 and 7 to induce apoptosis. Intrinsic apoptosis (right) is regulated by the Bcl-2 family of proteins. In response to apoptotic stimuli, BH3-only proteins are upregulated and bind to the pro-survival proteins (Bcl-2, Bcl-XL and Mcl-1) to displace Bax and Bak which then cause mitochondrial outer membrane permeabilization (MOMP) resulting in a release of cytochrome C and activation of the apoptosome (a complex containing caspase 9, Apaf-1 and cytochrome c). The apoptosome then catalytically cleaves caspases 3/7 to induce apoptosis. Created with BioRender.

Fig. 2. Bcl-2 family regulation of intrinsic apoptosis.

A In the absence of stress, the prosurvival Bcl-2 proteins bind to and inhibit Bax and Bak to restrain apoptosis. Bcl-2, Bcl-W, Bcl-X_L, Bfl-1 and Mcl-1 all have inhibitory action against Bax (indicated in purple) whereas only Bcl-X_L, Bfl-1 and Mcl-1 inhibit Bak (indicated in orange). B Stress stimuli upregulates BH3-only proteins such as Puma, Bim, Bid, Noxa or Bad (shown in red) which inhibit the pro-survival proteins by binding to them via their BH3-domains. Puma, Bim and Bid can inhibit all five of these proteins whereas Bad is specific for Bcl-2, Bcl-W and Bcl-X_L, and Noxa inhibits Bfl-1 and Mcl-1 only. Created with BioRender.