2. Academic Validation
  3. Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor

Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor

  • Cancer Discov. 2019 Jul;9(7):926-943. doi: 10.1158/2159-8290.CD-18-0903.
Ciric To  # 1 2 3,  Jaebong Jang  # 4 5,  Ting Chen 1,  Eunyoung Park 4 5,  Mierzhati Mushajiang 1,  Dries J H De Clercq 4 5,  Man Xu 6,  Stephen Wang 6,  Michael D Cameron 7,  David E Heppner 4 5,  Bo Hee Shin 1 2 3,  Thomas W Gero 4 5,  Annan Yang 2,  Suzanne E Dahlberg 8,  Kwok-Kin Wong 1 2 3 6,  Michael J Eck 9 5,  Nathanael S Gray 9 5,  Pasi A Jänne 10 2 3 6
Affiliations

Affiliations

  • 1 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
  • 6 Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • 7 Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida.
  • 8 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 9 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu nathanael_gray@dfci.harvard.edu michael_eck@dfci.harvard.edu.
  • 10 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu nathanael_gray@dfci.harvard.edu michael_eck@dfci.harvard.edu.
  • # Contributed equally.
PMID: 31092401 DOI: 10.1158/2159-8290.CD-18-0903
Abstract

Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. In this study, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFRL858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR. The combination of osimertinib and JBJ-04-125-02 results in an increase in Apoptosis, a more effective inhibition of cellular growth, and an increased efficacy in vitro and in vivo compared with either single agent alone. Collectively, our findings suggest that the combination of a covalent mutant-selective ATP-competitive inhibitor and an allosteric EGFR inhibitor may be an effective therapeutic approach for patients with EGFR-mutant lung Cancer. SIGNIFICANCE: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant lung Cancer is limited by acquired drug resistance, thus highlighting the need for alternative strategies to inhibit EGFR. Here, we identify a mutant EGFR allosteric inhibitor that is effective as a single agent and in combination with the EGFR TKI osimertinib.This article is highlighted in the In This Issue feature, p. 813.

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