Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor

TLDR

Allosteric kinase inhibitors target distinct sites and offer a complementary strategy to ATP‑competitive EGFR TKIs, yet EGFR dimerization and acquired resistance limit TKI efficacy, highlighting the need for alternative approaches. The study aims to identify and evaluate the mutant‑selective EGFR allosteric inhibitor JBJ‑04‑125‑02 for its ability to inhibit proliferation and mutant EGFR signaling in vitro and in vivo. The authors assess JBJ‑04‑125‑02 alone and with osimertinib, measuring its impact on mutant EGFR signaling, cell proliferation, apoptosis, and tumor growth in vitro and in vivo. Osimertinib markedly enhances JBJ‑04‑125‑02 binding to mutant EGFR, and their combination increases apoptosis, suppresses cellular growth, and improves efficacy in vitro and in vivo compared to either agent alone, suggesting a promising therapeutic strategy for EGFR‑mutant lung cancer. The article is highlighted in the journal’s “In This Issue” feature (p.

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.