Title | GCN2 kinase activation by ATP-competitive kinase inhibitors. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Tang CP, Clark O, Ferrarone JR, Campos C, Lalani AS, Chodera JD, Intlekofer AM, Elemento O, Mellinghoff IK |
Journal | Nat Chem Biol |
Volume | 18 |
Issue | 2 |
Pagination | 207-215 |
Date Published | 2022 Feb |
ISSN | 1552-4469 |
Keywords | Adenosine Triphosphate, Antineoplastic Agents, Cell Line, Tumor, CRISPR-Cas Systems, Drug Delivery Systems, Gene Deletion, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Protein Kinase Inhibitors, Quinolines |
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. |
DOI | 10.1038/s41589-021-00947-8 |
Alternate Journal | Nat Chem Biol |
PubMed ID | 34949839 |
PubMed Central ID | PMC9549920 |
Grant List | F31 CA239401 / CA / NCI NIH HHS / United States R35 NS105109 / NS / NINDS NIH HHS / United States R01 CA194547 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States UL1 TR002384 / TR / NCATS NIH HHS / United States R01 GM121505 / GM / NIGMS NIH HHS / United States |