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

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.

• Authors: Ciric To, Tyler S Beyett, Jaebong Jang, William W Feng, Magda Bahcall, Heidi M Haikala, Bo H Shin, David E Heppner, Jaimin K Rana, Brittaney A Leeper, Kara M Soroko, Michael J Poitras, Prafulla C Gokhale, Yoshihisa Kobayashi, Kamal Wahid, Kari J Kurppa, Thomas W Gero, Michael D Cameron, Atsuko Ogino, Mierzhati Mushajiang, Chunxiao Xu, Yanxi Zhang, David A Scott, Michael J Eck, Nathanael S Gray, Pasi A Jänne
• Journal: Nature cancer (Nat Cancer) Vol. 3 Issue 4 Pg. 402-417 (04 2022) ISSN: 2662-1347 [Electronic] England
• PMID: 35422503 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

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

Topics

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