High-throughput approaches to uncover synergistic drug combinations in leukemia

Emma J Chory; Meng Wang; Michele Ceribelli; Aleksandra M Michalowska; Stefan Golas; Erin Beck; Carleen Klumpp-Thomas; Lu Chen; Crystal McKnight; Zina Itkin; Kelli M Wilson; David Holland; Sanjay Divakaran; James Bradner; Javed Khan; Berkley E Gryder; Craig J Thomas; Benjamin Z Stanton

doi:10.1016/j.slasd.2023.04.004

High-throughput approaches to uncover synergistic drug combinations in leukemia

SLAS Discov. 2023 Jun;28(4):193-201. doi: 10.1016/j.slasd.2023.04.004. Epub 2023 Apr 29.

Authors

Emma J Chory¹, Meng Wang², Michele Ceribelli³, Aleksandra M Michalowska³, Stefan Golas⁴, Erin Beck³, Carleen Klumpp-Thomas³, Lu Chen³, Crystal McKnight³, Zina Itkin³, Kelli M Wilson³, David Holland³, Sanjay Divakaran⁵, James Bradner⁶, Javed Khan⁷, Berkley E Gryder⁸, Craig J Thomas⁹, Benjamin Z Stanton¹⁰

Affiliations

¹ Media Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.. Electronic address: emma.chory@duke.edu.
² Nationwide Children's Hospital, Center for Childhood Cancer and Blood Diseases, Columbus, OH, USA.
³ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
⁴ Media Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Cardio-Oncology Program, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, United States.
⁹ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁰ Nationwide Children's Hospital, Center for Childhood Cancer and Blood Diseases, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Biological Chemistry & Pharmacology, The Ohio State University College of Medicine, Columbus, OH, USA.. Electronic address: Benjamin.Stanton@nationwidechildrens.org.

PMID: 37121274
PMCID: PMC10449086 (available on 2024-06-01)
DOI: 10.1016/j.slasd.2023.04.004

Abstract

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Keywords: Acute myeloid leukemia; Combination index; Combination therapy; Epigenetics; Open-source automation; Precision medicine; Synergy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Drug Combinations
Drug Evaluation, Preclinical
Histone-Lysine N-Methyltransferase
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Myeloid-Lymphoid Leukemia Protein* / metabolism

Substances

Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Drug Combinations

Abstract

Publication types

MeSH terms

Substances

Grants and funding