Pathways and mechanisms of venetoclax resistance

Abstract

The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-X_L and MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current 'BH3 profiling' techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-X_L and MCL-1 is eagerly awaited.

Keywords: BCL-2; BCL-XL; MCL-1; Venetoclax; rational combinations; resistance.

Figure 1

Potential mechanism of action of ABT-199 (venetoclax). Venetoclax binds to the BH3-binding groove of BCL-2 and displaces Bim and other BH3-only proteins that are normally sequestered by this pro-survival (anti-apoptotic) protein. These BH3-only proteins are thus freed to activate the apoptosis effectors, Bax and Bak. Bax/Bak activation then leads to their oligomerization and mitochondrial outer membrane permeabilization. This commits the cell to apoptosis through the mitochondrial pathway, which is triggered by the activation of caspases. Modified, with permission, from ref. [51].