Article
作者: Haikala, Heidi M ; Scott, David A ; Mushajiang, Mierzhati ; Eck, Michael J ; Feng, William W ; Leeper, Brittaney A ; Heppner, David E ; To, Ciric ; Gokhale, Prafulla C ; Xu, Chunxiao ; Bahcall, Magda ; Gray, Nathanael S ; Kobayashi, Yoshihisa ; Jänne, Pasi A ; Shin, Bo H ; Wahid, Kamal ; Poitras, Michael J ; Gero, Thomas W ; Ogino, Atsuko ; Cameron, Michael D ; Soroko, Kara M ; Jang, Jaebong ; Zhang, Yanxi ; Beyett, Tyler S ; Rana, Jaimin K ; Kurppa, Kari J
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.