Abstract
Responses to kinase-inhibitor therapy in AML are frequently short-lived due to the rapid development of resistance, limiting the clinical efficacy. Combination therapy may improve initial therapeutic responses by targeting pathways used by leukemia cells to escape monotherapy. Here we report that combined inhibition of KIT and lysine-specific demethylase 1 (LSD1) produces synergistic cell death in KIT-mutant AML cell lines and primary patient samples. This drug combination evicts both MYC and PU.1 from chromatin driving cell cycle exit. Using a live cell biosensor for AKT activity, we identify early adaptive changes in kinase signaling following KIT inhibition that are reversed with the addition of LSD1 inhibitor via modulation of the GSK3a/b axis. Multi-omic analyses, including scRNA-seq, ATAC-seq and CUT&Tag, confirm these mechanisms in primary KIT-mutant AML. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML.
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Data availability
The Gene Expression Omnibus (GEO) accession number for all sequencing data reported in this paper is GSE182150. Other data generated in this study are available within the article and its supplementary data files or available from the corresponding author on reasonable request.
Code availability
The code used in this manuscript is publicly available through the programs listed above.
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Acknowledgements
We thank the following OHSU core facilities for their assistance: Advanced Light Microscopy, Flow Cytometry Shared Resource, Massive Parallel Sequencing Shared Resource, ExaCloud Cluster Computational Resource, and the Advanced Computing Center.
Author contributions
BMC, TPB, DJC, BJD, and JEM designed research; BMC, JEM, AT, MT, YHT, and TPB performed research; BMC, TPB, JV, GLK, WMY, WH, DJC, JE, Y.HT and TAL contributed new reagents/analytic tools; BMC, YHT, GBM, TPB, BJD, and JEM analyzed data; BMC wrote manuscript; BMC, TPB, and JEM reviewed and edited the manuscript.
Funding
Funding was provided by an American Society of Hematology Research Restart Award, an American Society of Hematology Scholar Award and 1 K08 CA245224 from NCI awarded to T.P.B. The Functional Proteomics RPPA Core is supported by MD Anderson Cancer Center Support Grant # 5 P30 CA016672-40.
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BJD -- SAB: Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Monojul (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Iterion Therapeutics, Third Coast Therapeutics, GRAIL (SAB inactive); Scientific Founder: MolecularMD (inactive, acquired by ICON); Board of Directors & Stock: Amgen; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Founder: VB Therapeutics; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license). J.E.M. -- SAB: Ionis pharmaceuticals. WMY -- former employee of Abreos Biosciences, Inc. and was compensated in part with common stock options. Pursuant to the merger and reorganization agreement between Abreos Biosciences, Inc. and Fimafeng, Inc., WMY surrendered all of his common stock options in 03/2021. The other authors do not have conflicts of interest, financial or otherwise.
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Curtiss, B.M., VanCampen, J., Macaraeg, J. et al. PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia. Leukemia 36, 1781–1793 (2022). https://doi.org/10.1038/s41375-022-01594-1
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DOI: https://doi.org/10.1038/s41375-022-01594-1