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

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

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. DavidA_Scott@dfci.harvard.edu.
  • 13 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. DavidA_Scott@dfci.harvard.edu.
  • 14 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. michael_eck@dfci.harvard.edu.
  • 15 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. michael_eck@dfci.harvard.edu.
  • 16 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. nathanael_gray@dfci.harvard.edu.
  • 17 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. nathanael_gray@dfci.harvard.edu.
  • 18 Department of Medicinal Chemistry and Department of Chemistry and Systems Biology, Stanford University, Stanford, CA, USA. nathanael_gray@dfci.harvard.edu.
  • 19 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. pasi_janne@dfci.harvard.edu.
  • 20 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. pasi_janne@dfci.harvard.edu.
  • 21 Department of Medicine, Harvard Medical School, Boston, MA, USA. pasi_janne@dfci.harvard.edu.
  • # Contributed equally.
PMID: 35422503 DOI: 10.1038/s43018-022-00351-8
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.

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