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Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib

Departments of ¹ Translational Medicine, ² Oncology Biology, ³ Biochemical and Cellular Targets, and ⁴ Computational, Analytical, and Structural Sciences; and ⁵ Discovery Technology Group, GlaxoSmithKline, Collegeville, Pennsylvania and Research Triangle Park, North Carolina

Requests for reprints: Tona M. Gilmer, Department of Translational Medicine, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709. Phone: 919-483-2100; Fax: 919-315-3749; E-mail: tona.m.gilmer{at}gsk.com.

The goal of this study was to characterize the effects of non–small cell lung carcinoma (NSCLC)-associated mutations in epidermal growth factor receptor (EGFR/ErbB1) and HER2 (ErbB2) on interactions with the dual tyrosine kinase inhibitor lapatinib. Biochemical studies show that commonly observed variants of EGFR [G719C, G719S, L858R, L861Q, and 746–750 (del15)] are enzyme activating, increasing the tyrosine kinase V_max and increasing the K_m^(app) for ATP. The point mutations G719C and L861Q had minor effects on lapatinib K_is, whereas EGFR mutations L858R and del15 had a higher K_i for lapatinib than wild-type EGFR. Structural analysis of wild-type EGFR-lapatinib complexes and modeling of the EGFR mutants were consistent with these data, suggesting that loss of structural flexibility and possible stabilization of the active-like conformation could interfere with lapatinib binding, particularly to the EGFR deletion mutants. Furthermore, EGFR deletion mutants were relatively resistant to lapatinib-mediated inhibition of receptor autophosphorylation in recombinant cells expressing the variants, whereas EGFR point mutations had a modest or no effect. Of note, EGFR T790M, a receptor variant found in patients with gefitinib-resistant NSCLC, was also resistant to lapatinib-mediated inhibition of receptor autophosphorylation. Two HER2 insertional variants found in NSCLC were less sensitive to lapatinib inhibition than two HER2 point mutants. The effects of lapatinib on the proliferation of human NSCLC tumor cell lines expressing wild-type or variant EGFR and HER2 cannot be explained solely on the basis of the biochemical activity or receptor autophosphorylation in recombinant cells. These data suggest that cell line genetic heterogeneity and/or multiple determinants modulate the role played by EGFR/HER2 in regulating cell proliferation. [Cancer Res 2008;68(2):571–9]