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Tang CP, Clark O, Ferrarone JR, et al. GCN2 kinase activation by ATP-competitive kinase inhibitors. Nat Chem Biol. 2021;doi: 10.1038/s41589-021-00947-8.
Tang, C. P., Clark, O., Ferrarone, J. R., Campos, C., Lalani, A. S., Chodera, J. D., Intlekofer, A. M., Elemento, O., & Mellinghoff, I. K. (2021). GCN2 kinase activation by ATP-competitive kinase inhibitors. Nature chemical biology, . https://doi.org/10.1038/s41589-021-00947-8
Tang, Colin P, et al. "GCN2 kinase activation by ATP-competitive kinase inhibitors." Nature chemical biology vol. (2021). doi: https://doi.org/10.1038/s41589-021-00947-8
Tang CP, Clark O, Ferrarone JR, Campos C, Lalani AS, Chodera JD, Intlekofer AM, Elemento O, Mellinghoff IK. GCN2 kinase activation by ATP-competitive kinase inhibitors. Nat Chem Biol. 2021 Dec 23; doi: 10.1038/s41589-021-00947-8. Epub 2021 Dec 23. PMID: 34949839.
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Nat Chem Biol. 2021 Dec 23; doi: 10.1038/s41589-021-00947-8. Epub 2021 Dec 23.

GCN2 kinase activation by ATP-competitive kinase inhibitors.

Nature chemical biology

Colin P Tang, Owen Clark, John R Ferrarone, Carl Campos, Alshad S Lalani, John D Chodera, Andrew M Intlekofer, Olivier Elemento, Ingo K Mellinghoff

Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  2. Pharmacology Program, Weill Cornell Medicine, New York, NY, USA.
  3. Caryl and Israel Englander Institute for Precision Medicine and Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  4. Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  5. Puma Biotechnology, Los Angeles, CA, USA.
  6. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  8. Physics and Biophysics Program, Weill Cornell Medicine, New York, NY, USA.
  9. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  10. Pharmacology Program, Weill Cornell Medicine, New York, NY, USA. [email protected].
  11. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].

PMID: 34949839 DOI: 10.1038/s41589-021-00947-8

Abstract

Small-molecule kinase inhibitors represent a major group of cancer therapeutics, but tumor responses are often incomplete. To identify pathways that modulate kinase inhibitor response, we conducted a genome-wide knockout (KO) screen in glioblastoma cells treated with the pan-ErbB inhibitor neratinib. Loss of general control nonderepressible 2 (GCN2) kinase rendered cells resistant to neratinib, whereas depletion of the GADD34 phosphatase increased neratinib sensitivity. Loss of GCN2 conferred neratinib resistance by preventing binding and activation of GCN2 by neratinib. Several other Food and Drug Administration (FDA)-approved inhibitors, such erlotinib and sunitinib, also bound and activated GCN2. Our results highlight the utility of genome-wide functional screens to uncover novel mechanisms of drug action and document the role of the integrated stress response (ISR) in modulating the response to inhibitors of oncogenic kinases.

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

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