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-XL 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-XL and MCL-1 is eagerly awaited.

T-PLL: another check on the venetoclax list?

“…Ex vivo sensitivity to venetoclax correlated with levels of expression of BCL-2 protein, but not with levels of BCL extra long (BCL-XL) or myeloid cell leukemia 1 (MCL-1), the 2 other major antiapoptotic proteins in the BCL-2 family. Levels of MCL-1, a major mediator of resistance to venetoclax, 4 inversely correlated with those of BCL-2. Based on these preclinical efficacy data, the investigators administered venetoclax on a compassionate-use basis to 2 patients with R/R T-PLL, both of whose cells exhibited ex vivo sensitivity to venetoclax.…”

“…Indeed, given the central role of BCL-2 in the regulation of apoptosis, it is not surprising that venetoclax acts as a universal apoptosis sensitizer, lending itself to a very large number of rational combinations across tumor types. 4 As far as single-agent activity of venetoclax is concerned, an important determinant of the same is the extent of dependence of the specific tumor type on BCL-2 for survival, and the relative importance of other antiapoptotic BCL-2 family proteins, specifically BCL-XL and MCL-1. 4 For example, BH3 profiling has revealed a high degree of dependence of early T-cell precursor acute lymphoblastic leukemia (ALL) on BCL-2, correlating with in vitro and in vivo sensitivity to venetoclax.…”

“…4 As far as single-agent activity of venetoclax is concerned, an important determinant of the same is the extent of dependence of the specific tumor type on BCL-2 for survival, and the relative importance of other antiapoptotic BCL-2 family proteins, specifically BCL-XL and MCL-1. 4 For example, BH3 profiling has revealed a high degree of dependence of early T-cell precursor acute lymphoblastic leukemia (ALL) on BCL-2, correlating with in vitro and in vivo sensitivity to venetoclax. 8 Similarly, even though the majority of pediatric ALLs in xenograft studies seem to require…”

“…One of the mechanisms through which CDK9 inhibitors like SNS-032 induce cell death is by transcriptionally downregulating MCL-1, and the combination of CDK9 inhibitors with venetoclax or navitoclax is a well-recognized synergistic strategy. 4 The strength of the study by Boidol and colleagues lies in the clinical responses to venetoclax they describe. However, the underlying biologic heterogeneity of T-PLL is apparent even in these 2 cases, which differed markedly in terms of time to response and dose dependence of the clinical response.…”

Untitled

“…Loss of wild-type p53 activity is thought to be a major predictor of failure to respond to chemotherapy in a wide variety of malignant neoplasms [1]. It is increasingly recognised that different neoplasm types display different degrees of addiction to individual Bcl-2 family proteins in particular [2].…”