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

The upregulation of BCL2 and BCL-XL, two proteins in the BCL2 family of proteins, leads to a disproportional expression of pro-death and pro-survival proteins in favor of leukemia survival, tumorigenesis, and chemoresistance.

In different subsets of acute lymphoblastic leukemia (ALL), the proportion of these two 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/-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/-XL inhibition was observed specifically in T-ALL samples. This observation was confirmed by BH3 profiling, demonstrating BCL2/-XL co-dependence 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/-XL inhibitor AZD0466 outperforms single BCL2 inhibition by venetoclax in T-ALL.

These findings facilitate the translation of dual BCL2/-XL inhibitors into ALL clinical trials, either alone or in combination with standard- of- care chemotherapy and immune therapies.