An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer

Janne and colleagues discover and characterize an allosteric EGFR inhibitor with efficacy against therapy-resistant mutations and show preclinical efficacy as monotherapy and in combination in patient-derived xenograft models. 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.

Automated summary

Researchers have discovered a new EGFR inhibitor, JBJ-09-063, which shows efficacy against therapy-resistant mutations in EGFR-mutant lung cancer. The study also found that the resistance to JBJ-09-063 is caused by EGFR homo- or heterodimerization and specific mutations.