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Research Articles: Therapeutics, Targets, and Development

The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor

Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Daniel A. Haber and Jeffrey Settleman, Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown 02129, MA. Phone: 617-724-9556; Fax: 617-726-7808. E-mail: haber{at}helix.mgh.harvard.edu and settlema{at}helix.mgh.harvard.edu

Abstract

Patients with non–small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) kinase domain tend to respond well to the tyrosine kinase inhibitors, gefitinib and erlotinib. However, following clinical response, these patients typically relapse within a year of treatment. In many cases, resistance is caused by an acquired secondary EGFR kinase domain mutation, T790M. In vitro studies have shown that a new class of EGFR-irreversible inhibitors could overcome the resistance conferred by T790M. Clinical trials are under way to examine the efficacy of one of these inhibitors, HKI-272, in patients with NSCLC who initially responded to gefitinib/erlotinib and subsequently relapsed. To anticipate the possibility that patients who respond to irreversible inhibitors will develop secondary resistance to such inhibitors, as has been seen in other similar settings, we modeled acquired resistance to the dual EGFR/HER2-irreversible tyrosine kinase inhibitor HKI-272 in a NSCLC cell culture model. We found that HKI-272–resistant clones fall into two biochemical groups based on the retention of EGFR phosphorylation in the presence of the drug. Cells that retain phosphorylated EGFR have acquired the secondary mutation T790M. Moreover, HKI-272 can overcome T790M resistance only at suprapharmacologic concentrations. We further model mutations at EGFR C797 as a mechanism of resistance to irreversible EGFR inhibitors and show that although these mutants are resistant to the irreversible inhibitor, they retain erlotinib sensitivity. Our findings suggest that HKI-272 treatment at maximally tolerated dosing may lead to the emergence of T790M-mediated resistance, whereas treatment with a more potent irreversible inhibitor could yield a resistance mutation at EGFR C797. [Mol Cancer Ther 2008;7(4):874–9]

Grant support: NIH grants R01 CA115830-02 (J. Settleman and D.A. Haber) and P01 CA95281 (D.A. Haber), the V Foundation Award (J. Settleman), the Doris Duke Foundation Distinguished Clinical Investigator for Cancer Research Award (D.A. Haber), and the Tosteson Postdoctoral Fellowship Award from the Massachusetts Biomedical Research Corporation (N. Godin-Heymann).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for N. Godin-Heymann: Signal Transduction Laboratory, Cancer Research UK, 44 Lincoln's Inn Field, London NW3 5PL, United Kingdom.

Received 12/10/07; accepted 2/ 4/08.