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

Nat Cancer. 2022 Apr;3(4):402-417. doi: 10.1038/s43018-022-00351-8. Epub 2022 Apr 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / therapeutic use
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Mutation
  • Protein Kinase Inhibitors / pharmacology


  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • EGFR protein, human
  • ErbB Receptors