GCN2 kinase activation by ATP-competitive kinase inhibitors.
Colin P TangOwen ClarkJohn R FerraroneCarl CamposAlshad S LalaniJohn D ChoderaAndrew M IntlekoferOlivier ElementoIngo K MellinghoffPublished in: Nature chemical biology (2021)
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.
Keyphrases
- genome wide
- small molecule
- induced apoptosis
- drug administration
- positive breast cancer
- dna methylation
- cell cycle arrest
- tyrosine kinase
- protein kinase
- signaling pathway
- gene expression
- renal cell carcinoma
- papillary thyroid
- copy number
- advanced non small cell lung cancer
- squamous cell
- climate change
- adverse drug
- dna binding