Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia
Document Type
Article
Publication Date
3-2021
Keywords
JMG
JAX Source
Nat Cancer 2021 Mar; 2(3):340-356
Volume
2
Issue
3
First Page
340
Last Page
356
DOI
10.1038/s43018-021-00177-w
Abstract
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.
Recommended Citation
Hashimoto M,
Saito Y,
Nakagawa R,
Ogahara I,
Takagi S,
Takata S,
Amitani H,
Endo M,
Yuki H,
Ramilowski JA,
Shultz LD,
Al E.
Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia Nat Cancer 2021 Mar; 2(3):340-356