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


CONCLUSIONS
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.
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.
Annette O
AO
Walter
Robert Tjin Tham
RT
Sjin
Henry J
HJ
Haringsma
Kadoaki
K
Ohashi
Jing
J
Sun
Kwangho
K
Lee
Aleksandr
A
Dubrovskiy
Matthew
M
Labenski
Zhendong
Z
Zhu
Zhigang
Z
Wang
Michael
M
Sheets
Thia
T
St Martin
Russell
R
Karp
Dan
D
van Kalken
Prasoon
P
Chaturvedi
Deqiang
D
Niu
Mariana
M
Nacht
Russell C
RC
Petter
William
W
Westlin
Kevin
K
Lin
Sarah
S
Jaw-Tsai
Mitch
M
Raponi
Terry
T
Van Dyke
Jeff
J
Etter
Zoe
Z
Weaver
William
W
Pao
Juswinder
J
Singh
Andrew D
AD
Simmons
Thomas C
TC
Harding
Andrew
A
Allen
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D000178:Acrylamides; D000970:Antineoplastic Agents; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000589977:rociletinib; D066246:ErbB Receptors