6DUK

Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor.

(2019) Cancer Discov 9: 926-943

• PubMed: 31092401 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1158/2159-8290.CD-18-0903
• Primary Citation of Related Structures:  
  6DUK


• PubMed 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 EGFR ^{L858R/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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Organizational Affiliation: 

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.