| Literature DB >> 35422503 |
Ciric To1,2,3, Tyler S Beyett4,5, Jaebong Jang4,5,6, William W Feng1,2,3, Magda Bahcall1,2,3, Heidi M Haikala1,2,3, Bo H Shin1,2,3, David E Heppner4,5,7, Jaimin K Rana4,5, Brittaney A Leeper8, Kara M Soroko8, Michael J Poitras8, Prafulla C Gokhale8, Yoshihisa Kobayashi1,2,3,9, Kamal Wahid10, Kari J Kurppa1,2,3,10, Thomas W Gero4,5, Michael D Cameron11, Atsuko Ogino1,2,3, Mierzhati Mushajiang1,2,3, Chunxiao Xu1,2,3, Yanxi Zhang1,2,3, David A Scott12,13, Michael J Eck14,15, Nathanael S Gray16,17,18, Pasi A Jänne19,20,21.
Abstract
Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.Entities:
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Year: 2022 PMID： 35422503 PMCID： PMC9248923 DOI： 10.1038/s43018-022-00351-8
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347