2. Academic Validation
  3. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC

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

  • Cancer Discov. 2013 Dec;3(12):1404-15. doi: 10.1158/2159-8290.CD-13-0314.
Annette O Walter 1,  Robert Tjin Tham Sjin,  Henry J Haringsma,  Kadoaki Ohashi,  Jing Sun,  Kwangho Lee,  Aleksandr Dubrovskiy,  Matthew Labenski,  Zhendong Zhu,  Zhigang Wang,  Michael Sheets,  Thia St Martin,  Russell Karp,  Dan van Kalken,  Prasoon Chaturvedi,  Deqiang Niu,  Mariana Nacht,  Russell C Petter,  William Westlin,  Kevin Lin,  Sarah Jaw-Tsai,  Mitch Raponi,  Terry Van Dyke,  Jeff Etter,  Zoe Weaver,  William Pao,  Juswinder Singh,  Andrew D Simmons,  Thomas C Harding,  Andrew Allen
Affiliations

Affiliation

  • 1 1Clovis Oncology Inc., San Francisco, California; 2Celgene Avilomics Research, Bedford, Massachusetts; 3Division of Hematology-Oncology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 4Mouse Cancer Genetics Program; and 5Center for Advanced Preclinical Research, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, Maryland.
PMID: 24065731 DOI: 10.1158/2159-8290.CD-13-0314
Abstract

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 specifically 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 fi rst 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.

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