An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer PMID: 35422503

ADC Targets in Oncology

2026-04-10

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.

Ciric To ^# ¹ ² ³ , Tyler S Beyett ^# ⁴ ⁵ , Jaebong Jang ^# ⁴ ⁵ ⁶ , William W Feng ¹ ² ³ , Magda Bahcall ¹ ² ³ , Heidi M Haikala ¹ ² ³ , Bo H Shin ¹ ² ³ , David E Heppner ⁴ ⁵ ⁷ , Jaimin K Rana ⁴ ⁵ , Brittaney A Leeper ⁸ , Kara M Soroko ⁸ , Michael J Poitras ⁸ , Prafulla C Gokhale ⁸ , Yoshihisa Kobayashi ¹ ² ³ ⁹ , Kamal Wahid ¹⁰ , Kari J Kurppa ¹ ² ³ ¹⁰ , Thomas W Gero ⁴ ⁵ , Michael D Cameron ¹¹ , Atsuko Ogino ¹ ² ³ , Mierzhati Mushajiang ¹ ² ³ , Chunxiao Xu ¹ ² ³ , Yanxi Zhang ¹ ² ³ , David A Scott ¹² ¹³ , Michael J Eck ¹⁴ ¹⁵ , Nathanael S Gray ¹⁶ ¹⁷ ¹⁸ , Pasi A Jänne ¹⁹ ²⁰ ²¹

Affiliations

1. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3. Department of Medicine, Harvard Medical School, Boston, MA, USA.
4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
6. College of Pharmacy, Korea University, Sejong, Korea.
7. Department of Chemistry, University at Buffalo, Buffalo, NY, USA.
8. Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
9. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
10. Institute of Biomedicine, MediCity Research Laboratories, University of Turku, Turku, Finland.
11. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA.
12. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
13. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
14. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
15. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
16. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
17. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
18. Department of Medicinal Chemistry and Department of Chemistry and Systems Biology, Stanford University, Stanford, CA, USA. [email protected].
19. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
20. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
21. Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
# Contributed equally.

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.