1区 · 医学
Article
作者: Walter, Annette O. ; Sjin, Robert Tjin Tham ; Haringsma, Henry J. ; Ohashi, Kadoaki ; Sun, Jing ; Lee, Kwangho ; Dubrovskiy, Aleksandr ; Labenski, Matthew ; Zhu, Zhendong ; Wang, Zhigang ; Sheets, Michael ; St. Martin, Thia ; Karp, Russell ; van Kalken, Dan ; Chaturvedi, Prasoon ; Niu, Deqiang ; Nacht, Mariana ; Petter, Russell C. ; Westlin, William ; Lin, Kevin ; Jaw-Tsai, Sarah ; Raponi, Mitch ; Van Dyke, Terry ; Etter, Jeff ; Weaver, Zoe ; Pao, William ; Singh, Juswinder ; Simmons, Andrew D. ; Harding, Thomas C. ; Allen, Andrew
UNLABELLED: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.