RRC ID 52399
Author Niessen S, Dix MM, Barbas S, Potter ZE, Lu S, Brodsky O, Planken S, Behenna D, Almaden C, Gajiwala KS, Ryan K, Ferre R, Lazear MR, Hayward MM, Kath JC, Cravatt BF.
Title Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors.
Journal Cell Chem Biol
Abstract Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may affect drug activity and safety.
Volume 24(11)
Pages 1388-1400.e7
Published 2017-11-16
DOI 10.1016/j.chembiol.2017.08.017
PII S2451-9456(17)30315-X
PMID 28965727
PMC PMC5693604
MeSH 5'-Nucleotidase / chemistry 5'-Nucleotidase / genetics 5'-Nucleotidase / metabolism Acrylamides Aniline Compounds Animals Cathepsins / chemistry Cathepsins / metabolism Cell Line, Tumor Checkpoint Kinase 2 / chemistry Checkpoint Kinase 2 / genetics Checkpoint Kinase 2 / metabolism Cysteine / chemistry ErbB Receptors / genetics ErbB Receptors / metabolism* GPI-Linked Proteins / chemistry GPI-Linked Proteins / genetics GPI-Linked Proteins / metabolism HEK293 Cells Humans Liver / metabolism Lysosomes / metabolism Mice Mice, Inbred C57BL Mutagenesis, Site-Directed Piperazines / chemistry Piperazines / metabolism Protein Kinase Inhibitors / chemistry* Protein Kinase Inhibitors / metabolism Proteome / analysis* Proteomics Rhodamines / chemistry Transplantation, Heterologous
IF 6.762
Times Cited 25
Human and Animal Cells PC-9(RCB4455)