Other
18 Authors
- Gray NS,
- Dahlberg SE,
- Gero TW,
- Yang A,
- Chen T,
- De Clercq DJH,
- Eck MJ,
- Cameron MD,
- Heppner DE,
- To C,
- Jänne PA,
- Park E,
- Mushajiang M,
- Wang S,
- Wong KK,
- Shin BH,
- Jang J,
- Xu M
| First Author | To C | Year | 2019 |
| Journal | Cancer Discov | Volume | 9 |
| Issue | 7 | Pages | 926-943 |
| PubMed ID | 31092401 | Mgi Jnum | J:277590 |
| Mgi Id | MGI:6324479 | Doi | 10.1158/2159-8290.CD-18-0903 |
| Citation | To C, et al. (2019) Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor. Cancer Discov 9(7):926-943 |
| abstractText | 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. |
