Abstract C189: CO-1686, an orally available, mutant-selective inhibitor of the epidermal growth factor receptor (EGFR), causes tumor shrinkage in non-small cell lung cancer (NSCLC) with T790M mutations.
Authors: Walter Annette O. , Tjin Robert , Haringsma Henry , Lin Kevin , Dubrovskiy Alex , Lee Kwangho , St. Martin Thia , Karp Russell , Zhu Zhendong , Niu Deqiang , Nacht Mariana , Petter Russell C. , Westlin William F. , Singh Juswinder , Raponi Mitch , Allen Andrew 
Published: June 2012

Introduction: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond well to EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by the development of resistance. The most common mechanism of resistance is a second site mutation within exon 20 of EGFR (T790M), observed in ∼50% of cases. Our goal was to develop a mutant-selective EGFR inhibitor that potently inhibits activating EGFR mutations as well as the T790M resistance mutation while sparing wild-type EGFR for the treatment of NSCLC patients. Such a drug has the potential to effectively treat first- and second-line NSCLC patients with EGFR mutations without causing the dose limiting toxicities associated with EGFR kinase inhibitors currently in clinical development.

Experimental procedures: Using structure-based drug design, we identified CO-1686, a covalent, irreversible small molecule, which selectively inhibits mutant EGFR. We assessed antitumor activity of CO-1686 both in vitro and in vivo in two NSCLC cell lines harboring EGFR mutations: H1975 (EGFR L858R/T790M) and HCC827 (EGFR delE746-A750). We evaluated inhibition of EGFR phosphorylation and downstream signaling by immunoblot analysis in cells and tissue samples. IHC staining on skin samples was performed to address effects on wild-type EGFR.

Results: CO-1686 is a potent inhibitor of cell proliferation and EGFR signaling in NSCLC cells harboring the single activating mutation EGFR delE746-A750 as well as the double mutation EGFR L858R/T790M. When administered orally, CO-1686 (3 − 100 mg/kg) significantly suppresses tumor growth of H1975 cells (L858R/T790M) in a dose-dependent manner causing tumor regressions at the highest dose (100 mg/kg) without affecting body weight. Erlotinib at the same dose exhibits no effect against H1975 xenografts. In HCC827 (delE746-A750) xenografts, both agents cause tumor shrinkage. In both NSCLC mouse models, inhibition of EGFR phosphorylation in tumors correlate with the observed anti-tumor activity, while no effect on EGFR signaling is observed in normal lung or skin tissues with CO-1686 treatment, confirming that CO-1686 does not inhibt wild-type EGFR.

Conclusions: Our results establish CO-1686 as a mutant-selective, wild-type sparing EGFR inhibitor with in vivo efficacy against tumors with activating EGFR mutations as well as the resistance mutation T790M. These data suggest that treatment with CO-1686 as a single agent can overcome T790M-mediated drug resistance in NSCLC. This hypothesis will be tested clinically.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C189.