Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells
Inhibitors targeting BCL-2 apoptotic proteins show significant promise for treating acute myeloid leukemia (AML), yet complete responses are observed in only about 20% of patients. This indicates that targeting BCL-2 alone may not be sufficient for achieving durable responses. In this study, we evaluated the effectiveness of coadministering the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib alongside the selective BCL-2 antagonist venetoclax in AML cells.
We found that tetracycline-inducible downregulation of BCL-2 significantly increased the sensitivity of MV4-11 and MOLM-13 AML cells to PI3K inhibition. The combination of venetoclax and GDC-0980 led to rapid and significant BAX mitochondrial translocation, cytochrome c release, and apoptosis across various AML cell lines. This was associated with the inactivation of AKT/mTOR and downregulation of MCL-1; notably, ectopic expression of MCL-1 provided substantial protection against this treatment.
Additionally, the combined treatment was effective against primary AML blasts from 17 patients, including those with different genetic abnormalities. Venetoclax and GDC-0980 together notably induced apoptosis in primitive CD34+/38-/123+ AML cell populations without affecting normal hematopoietic progenitor CD34+ cells. This regimen also showed efficacy against AML cells with intrinsic or acquired resistance to venetoclax, as well as those influenced by the tumor microenvironment.
In systemic AML xenograft mouse models, the combinatorial treatment significantly reduced AML growth and extended survival, while also decreasing tumor growth in two patient-derived xenograft models. The activity of venetoclax and GDC-0980 was partially reduced in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, although BIM-/- cells remained fully sensitive. Similar outcomes were observed with venetoclax alone in both in vitro and in vivo systemic xenograft models.
Overall, these findings demonstrate that the combination of venetoclax and GDC-0980 exerts potent anti-AML activity primarily through BAX, and to a lesser extent, BAK. This suggests that dual inhibition of BCL-2 and PI3K merits further investigation in AML treatment.
Significance: The combined use of clinically relevant PI3K and BCL-2 inhibitors may offer a promising approach for treating acute myeloid leukemia. Cancer Res; 78(11); 3075-86. ©2018 AACR.