AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death

• Published in: Cell death and differentiation 2024-04, Vol.31 (4), p.405-416
• Main Authors: Jia, Jia, Ji, Wenbo, Saliba, Antoine N., Csizmar, Clifford M., Ye, Kaiqin, Hu, Lei, Peterson, Kevin L., Schneider, Paula A., Meng, X. Wei, Venkatachalam, Annapoorna, Patnaik, Mrinal M., Webster, Jonathan A., Smith, B. Douglas, Ghiaur, Gabriel, Wu, Xinyan, Zhong, Jun, Pandey, Akhilesh, Flatten, Karen S., Deng, Qingmei, Wang, Hongzhi, Kaufmann, Scott H., Dai, Haiming
• Format: Article
• Language: English
• Subjects: 631/67; 631/80; 96/106; 96/2; 96/31; 96/95; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Aniline Compounds - pharmacology; Animals; Antitumor activity; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; bcl-Associated Death Protein - metabolism; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Cell Death - drug effects; Cell Line, Tumor; Dephosphorylation; Drug Synergism; Humans; Leukemia; Leukemia - drug therapy; Leukemia - metabolism; Leukemia - pathology; Life Sciences; Mcl-1 protein; Mice; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Peptide Fragments - pharmacology; Phosphorylation - drug effects; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Stem Cells; Sulfonamides - pharmacology; Thrombocytopenia; Toxicity; Tumor cell lines
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-024-01283-9

BH3 mimetics, including the BCL2/BCLX L /BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLX L inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLX L . Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.