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Cancer Discov. 2019 Jul;9(7):926-943. doi: 10.1158/2159-8290.CD-18-0903. Epub 2019 May 15.

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

Author information

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

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.

PMID:
31092401
PMCID:
PMC6664433
[Available on 2020-07-01]
DOI:
10.1158/2159-8290.CD-18-0903

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