Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M mediated resistance in NSCLC

Annette O. Walter, Robert Tjin Tham Sjin, Henry J. Haringsma, Jing Sun, Kadoaki Ohashi, Kwangho Lee, Aleksandr Dubrovskiy, Matthew Labenski, Zhigang Wang, Zhendong Zhu, Michael Sheets, Thia St Martin, Russell Karp, Dan van Kalken, Prasoon Chaturvedi, Deqiang Niu, Mariana Nacht, Russell C. Petter, Kevin Lin, William WestlinSarah Jaw-Tsai, Mitch Raponi, Terry Van Dyke, Jeff Etter, William Pao, Zoe Weaver, Juswinder Singh, Andrew D. Simmons, Thomas C. Harding, Andrew Allen

Research output: Contribution to journalArticlepeer-review

550 Citations (Scopus)


Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR T790M mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifi - cally targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR -mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC. SIGNIFICANCE: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the first drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR.

Original languageEnglish
Pages (from-to)1404-1415
Number of pages12
JournalCancer discovery
Issue number12
Publication statusPublished - Dec 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology


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