Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

TY - JOUR

T1 - Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

AU - Walter, Annette O

AU - Sjin, Robert Tjin Tham

AU - Haringsma, Henry J

AU - Ohashi, Kadoaki

AU - Sun, Jing

AU - Lee, Kwangho

AU - Dubrovskiy, Aleksandr

AU - Labenski, Matthew

AU - Zhu, Zhendong

AU - Wang, Zhigang

AU - Sheets, Michael

AU - St Martin, Thia

AU - Karp, Russell

AU - van Kalken, Dan

AU - Chaturvedi, Prasoon

AU - Niu, Deqiang

AU - Nacht, Mariana

AU - Petter, Russell C

AU - Westlin, William

AU - Lin, Kevin

AU - Jaw-Tsai, Sarah

AU - Raponi, Mitch

AU - Van Dyke, Terry

AU - Etter, Jeff

AU - Weaver, Zoe

AU - Pao, William

AU - Singh, Juswinder

AU - Simmons, Andrew D

AU - Harding, Thomas C

AU - Allen, Andrew

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

U2 - 10.1158/2159-8290.CD-13-0314

DO - 10.1158/2159-8290.CD-13-0314

M3 - Article

C2 - 24065731

SN - 1574-8928

VL - 3

SP - 1404

EP - 1415

JO - Recent Patents On Anti-Cancer Drug Discovery

JF - Recent Patents On Anti-Cancer Drug Discovery

IS - 12

M1 - N/A

ER -