Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL

Abstract

Targeting BCL-2, a key regulator of survival in B-cell malignancies including precursor B-cell acute lymphoblastic leukemia, has become a promising treatment strategy. However, given the redundancy of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, MCL-1), single targeting may not be sufficient. When analyzing the effects of BH3-mimetics selectively targeting BCL-XL and MCL-1 alone or in combination with the BCL-2 inhibitor venetoclax, heterogeneous sensitivity to either of these inhibitors was found in ALL cell lines and in patient-derived xenografts. Interestingly, some venetoclax-resistant leukemias were sensitive to the MCL-1-selective antagonist S63845 and/or BCL-XL-selective A-1331852 suggesting functional mutual substitution. Consequently, co-inhibition of BCL-2 and MCL-1 or BCL-XL resulted in synergistic apoptosis induction. Functional analysis by BH3-profiling and analysis of protein complexes revealed that venetoclax-treated ALL cells are dependent on MCL-1 and BCL-XL, indicating that MCL-1 or BCL-XL provide an Achilles heel in BCL-2-inhibited cells. The effect of combining BCL-2 and MCL-1 inhibition by venetoclax and S63845 was evaluated in vivo and strongly enhanced anti-leukemia activity was found in a pre-clinical patient-derived xenograft model. Our study offers in-depth molecular analysis of mutual substitution of BCL-2 family proteins in acute lymphoblastic leukemia and provides targets for combination treatment in vivo and in ongoing clinical studies.

Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia

“…Thus, this drug combination may sensitize cells with both survival proteins overexpressed and overcome the resistance to both drugs individually. Consistent with our findings, a recent study of venetoclax and S63845 (an alternate MCL-1 inhibitor) in diploid leukemias demonstrated synergistic anti-leukemia activity through the impaired binding of BCL-2 and MCL-1 to the apoptosis activator BIM 32 . Thus, for hypodiploid B-ALL, which has elevated levels of both BCL-2 and MCL-1, as well as the proapoptotic proteins (BIM, BAD, and/or PUMA) this drug combination may represent a promising targeted therapeutic approach.…”

“…Consistent with our findings, a recent study of venetoclax and S63845 (an alternate MCL-1 inhibitor) in diploid leukemias demonstrated synergistic anti-leukemia activity through the impaired binding of BCL-2 and MCL-1 to the apoptosis activator BIM. 32 Thus, for hypodiploid B-ALL, which has elevated levels of both BCL-2 and MCL-1, as well as the proapoptotic proteins (BIM, BAD, and/or PUMA) this drug combination may represent a promising targeted therapeutic approach. Given the cytotoxic rather than cytostatic effect of both venetoclax and dinaciclib, this combination provides a strong rationale for a complementary and effective therapeutic approach.…”

Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells

“…In concordance with our results demonstrating the selective senolytic effect on irradiated RPE-1 cells, a new study showing the selective senolytic effect of Venetoclax on radiotherapy-induced senescent sarcoma cell lines has been published [ 69 ], broadening the potential application range of Venetoclax. It should be noted that the combination of BCL-2 (Venetoclax) and MCL-1 (S63845) or BCL-XL (A-1331852) was effective against precursor B-cell acute lymphoblastic leukemia, as reported recently using patients' xenografts in mouse model [ 70 ].…”

Combination p53 activation and BCL-xL/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia

“…Excitingly, idasanutlin in combination with chemotherapy or venetoclax is currently progressing to phase I/II clinical trials for relapsed pediatric AML and ALL patients (NCT04029688). However, unlike AML blasts which are predominantly BCL-2 dependent [ 42 ], ALL blasts often exhibit anti-apoptotic dependence on both BCL-2 and BCL-x L [ 43 – 45 ]; with exception to specific subtypes [ 44 , 46 , 47 ]. Accordingly, Khaw and colleagues showed venetoclax to be effective against only a minority of B-ALL xenografts in vivo, whereas combined BCL-2/BCL-x L inhibition resulted in synergistic killing in most models [ 47 ].…”