Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors. Issue 11 (16th November 2017)

• Record Type: Journal Article
• Authors: Niessen, Sherry; Dix, Melissa M.; Barbas, Sabrina; Potter, Zachary E.; Lu, Shuyan; Brodsky, Oleg; Planken, Simon; Behenna, Douglas; Almaden, Chau; Gajiwala, Ketan S.; Ryan, Kevin; Ferre, RoseAnn; Lazear, Michael R.; Hayward, Matthew M.; Kath, John C.; Cravatt, Benjamin F.
• Is Part Of: Cell chemical biology. Volume 24:Issue 11(2017)
• Page Start: 1388
• Page End: 1400.e7
• Publication Date: 2017-11-16
• Subjects: proteomics -- chemical probes -- kinases -- T790M-EGFR -- covalent inhibitors -- cathepsins -- lysosomal accumulation; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.08.017
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Targets of covalent T790M-EGFR inhibitors identified in cancer cells Individual T790M-EGFR inhibitors have distinct off-targets Functional and ligandable cysteines are common sites of inhibitor reactivity Osimertinib inhibits cathepsins in living systems due to lysosomal accumulation Abstract : Niessen et al. explore the proteome-wide reactivity of third-generation T790M-EGFR inhibitors in human cancer cells and animal models through the development and application of chemical probes and quantitative mass spectrometry-based proteomic methods. These studies highlight the importance of performing global analyses of drug action in living systems to identify targets and off-targets that may affect efficacy and safety.