American Association for Cancer Research
21598290cd180903-sup-206657_2_supp_5491549_pqslp1.pdf (1.76 MB)

Figure S1 from Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor

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journal contribution
posted on 2023-04-03, 21:43 authored by Ciric To, Jaebong Jang, Ting Chen, Eunyoung Park, Mierzhati Mushajiang, Dries J.H. De Clercq, Man Xu, Stephen Wang, Michael D. Cameron, David E. Heppner, Bo Hee Shin, Thomas W. Gero, Annan Yang, Suzanne E. Dahlberg, Kwok-Kin Wong, Michael J. Eck, Nathanael S. Gray, Pasi A. Jänne

JBJ-04-125-02 is more potent than EAI045 and JBJ-02-112-05 in the presence of cetuximab and is effective in inhibiting EGFR-dependent proliferation and phosphorylation in L858R/ C797S Ba/F3 cells.



American Cancer Society

the Ildiko Medve and Adria Sai-Halasz EGFR Lung Cancer Research Fund

Balassiano Family Fund for Lung Cancer Research

Harvard Medical School

Klingenstein Third Generation Foundation

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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. 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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