GCN2 kinase activation by ATP-competitive kinase inhibitors Journal Article

   


Authors: Tang, C. P.; Clark, O.; Ferrarone, J. R.; Campos, C.; Lalani, A. S.; Chodera, J. D.; Intlekofer, A. M.; Elemento, O.; Mellinghoff, I. K.
Article Title: GCN2 kinase activation by ATP-competitive kinase inhibitors
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. [Figure not available: see fulltext.]. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: gene deletion; antineoplastic agents; antineoplastic agent; metabolism; protein kinase inhibitor; drug effect; cell line, tumor; drug delivery systems; protein kinase inhibitors; gene expression regulation; gene expression regulation, neoplastic; chemistry; glioblastoma; tumor cell line; adenosine triphosphate; drug delivery system; neratinib; quinolines; quinoline derivative; humans; human; crispr cas system; crispr-cas systems
Journal Title: Nature Chemical Biology
Volume: 18
Issue: 2
ISSN: 1552-4450
Publisher: Nature Publishing Group  
Date Published: 2022-02-01
Start Page: 207
End Page: 215
Language: English
DOI: 10.1038/s41589-021-00947-8
PUBMED: 34949839
PROVIDER: scopus
PMCID: PMC9549920
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85121592525&doi=10.1038%2fs41589-021-00947-8&partnerID=40&md5=86130dcc4e4c9e6a106412c174de05de
Notes: Article -- Export Date: 1 March 2022 -- Source: Scopus
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MSK Authors
  1. Ingo K Mellinghoff
    271 Mellinghoff
  2. Carl Campos
    37 Campos
  3. Owen Richard Clark
    5 Clark
  4. Andrew Michael Intlekofer
    97 Intlekofer
  5. John Damon Chodera
    120 Chodera
  6. Colin Tang
    1 Tang
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