Antileukemia efficacy of the dual BCL2/BCL-XL inhibitor AZD0466 in acute lymphoblastic leukemia preclinical models

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Abstract
The upregulation of B-cell lymphoma 2 (BCL2) and B-cell lymphoma–extra large (BCL-XL), 2 proteins in the BCL2 family of proteins, leads to a disproportional expression of prodeath and prosurvival proteins in favor of leukemia survival, tumorigenesis, and chemoresistance. In different subsets of acute lymphoblastic leukemia (ALL), the proportion of these 2 proteins varies, and their potential as therapeutic targets needs detailed characterization. Here, we investigated BCL2 and BCL-XL, the genes that encode BCL2 and BCL-XL, and their expression differences between B-cell acute lymphoblastic leukemia (B-ALL) and T-cell ALL (T-ALL). We also evaluated the therapeutic potential of targeting these proteins with AZD0466, a novel drug-dendrimer conjugate of the BCL2/BCL-XL inhibitor AZD4320, and with BCL2 inhibitor venetoclax (ABT-199). Gene expression and activity analyses supported by the protein expression patterns in ALL cell lines and primary samples demonstrated increased levels of BCL2 expression in B-ALL, with high sensitivity to venetoclax or AZD4320. In contrast, strong BCL-XL expression and sensitivity to dual BCL2/BCL-XL inhibition was observed specifically in T-ALL samples. This observation was confirmed by BH3 profiling, demonstrating BCL2/BCL-XL codependence in T-ALL and BCL2 dependence in B-ALL. In a mouse model of T-ALL, AZD0466 but not venetoclax reduced leukemic burden and prolonged survival without significant toxicities. Our findings therefore suggest that the novel dual BCL2/BCL-XL inhibitor AZD0466 outperforms single BCL2 inhibition by venetoclax in T-ALL. These findings facilitate the translation of dual BCL2/BCL-XL inhibitors into ALL clinical trials, either alone or in combination with standard-of-care chemotherapy and immune therapies.

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