Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia.
Mari HashimotoYoriko SaitoRyo NakagawaIkuko OgaharaShinsuke TakagiSadaaki TakataHanae AmitaniMikiko EndoHitomi YukiJordan A RamilowskiJessica SeverinRi-Ichiroh ManabeTakashi WatanabeKokoro OzakiAkiko KanekoHiroshi KajitaSaera FujikiKaori SatoTeruki HonmaNaoyuki UchidaTakehiro FukamiYasushi OkazakiOsamu OharaLeonard D ShultzMakoto YamadaShuichi TaniguchiParesh VyasMichiel de HoonYukihide MomozawaFumihiko IshikawaPublished in: Nature cancer (2021)
Aggressive therapy-resistant and refractory acute myeloid leukemia (AML) has an extremely poor outcome. By analyzing a large number of genetically complex and diverse, primary high-risk poor-outcome human AML samples, we identified specific pathways of therapeutic vulnerability. Through drug screens followed by extensive in vivo validation and genomic analyses, we found inhibition of cytosolic and mitochondrial anti-apoptotic proteins XIAP, BCL2 and MCL1, and a key regulator of mitosis, AURKB, as a vulnerability hub based on patient-specific genetic aberrations and transcriptional signatures. Combinatorial therapeutic inhibition of XIAP with an additional patient-specific vulnerability eliminated established AML in vivo in patient-derived xenografts (PDXs) bearing diverse genetic aberrations, with no signs of recurrence during off-treatment follow-up. By integrating genomic profiling and drug-sensitivity testing, this work provides a platform for a precision-medicine approach for treating aggressive AML with high unmet need.
Keyphrases
- acute myeloid leukemia
- copy number
- genome wide
- allogeneic hematopoietic stem cell transplantation
- climate change
- endothelial cells
- transcription factor
- high throughput
- gene expression
- dna methylation
- oxidative stress
- emergency department
- stem cells
- blood pressure
- adverse drug
- mesenchymal stem cells
- cell therapy
- anti inflammatory
- smoking cessation