Differential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors

David B. Chou, Brooke A. Furlong, Ryan R. Posey, Christos Kyprianou, Lucy R. O’Sullivan, Rhiannon David, Suzanne J. Randle, Urszula M. Polanska, Jon Travers, Jelena Urosevic, John N. Hutchinson, Jianwei Che, Anna M. Howley, Robert P. Hasserjian, Rachelle Prantil-Baun and Donald E. Ingber ()
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David B. Chou: Wyss Institute for Biologically Inspired Engineering at Harvard University
Brooke A. Furlong: Wyss Institute for Biologically Inspired Engineering at Harvard University
Ryan R. Posey: Wyss Institute for Biologically Inspired Engineering at Harvard University
Christos Kyprianou: Wyss Institute for Biologically Inspired Engineering at Harvard University
Lucy R. O’Sullivan: Wyss Institute for Biologically Inspired Engineering at Harvard University
Rhiannon David: AstraZeneca
Suzanne J. Randle: AstraZeneca
Urszula M. Polanska: AstraZeneca
Jon Travers: AstraZeneca
Jelena Urosevic: AstraZeneca
John N. Hutchinson: Harvard Chan Bioinformatics Core
Jianwei Che: Harvard Medical School
Anna M. Howley: Wyss Institute for Biologically Inspired Engineering at Harvard University
Robert P. Hasserjian: Massachusetts General Hospital
Rachelle Prantil-Baun: Wyss Institute for Biologically Inspired Engineering at Harvard University
Donald E. Ingber: Wyss Institute for Biologically Inspired Engineering at Harvard University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Drug-induced cytopenias are a prevalent and significant issue that worsens clinical outcomes and hinders the effective treatment of cancer. While reductions in blood cell numbers are classically associated with traditional cytotoxic chemotherapies, they also occur with newer targeted small molecules and the factors that determine the hematotoxicity profiles of oncologic drugs are not fully understood. Here, we explore why some Aurora kinase inhibitors cause preferential neutropenia. By studying drug responses of healthy human hematopoietic cells in vitro and analyzing existing gene expression datasets, we provide evidence that the enhanced vulnerability of neutrophil-lineage cells to Aurora kinase inhibition is caused by early developmental changes in ATP-binding cassette (ABC) transporter expression. These data show that hematopoietic cell-intrinsic expression of ABC transporters may be an important factor that determines how some Aurora kinase inhibitors affect the bone marrow.

Date: 2022
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DOI: 10.1038/s41467-022-33672-4

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