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The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272

Oncogene volume 26, pages 5023–5027 (2007)Cite this article

Abstract

Mutations in the ERBB2 gene were recently found in approximately 2% of primary non-small cell lung cancer (NSCLC) specimens; however, little is known about the functional consequences and the relevance to responsiveness to targeted drugs for most of these mutations. Here, we show that the major lung cancer-derived ERBB2 mutants, including the most frequent mutation, A775insYVMA, lead to oncogenic transformation in a cellular assay. Murine cells transformed with these mutants were relatively resistant to the reversible epidermal growth factor receptor (EGFR) inhibitor erlotinib, resembling the resistant phenotype found in cells carrying the homologous mutations in exon 20 of EGFR. However, the same cells were highly sensitive to the irreversible dual-specificity EGFR/ERBB2 kinase inhibitor HKI-272, as were those overexpressing wild-type ERBB2. Finally, the NSCLC cell line, Calu-3, overexpressing wild-type ERBB2 owing to a high-level amplification of the ERBB2 gene were highly sensitive to HKI-272. These results provide a rationale for treatment of patients with ERBB2-mutant or ERBB2-amplified lung tumors with HKI-272.

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Acknowledgements

RK Thomas is a Fellow of the International Association for the Study of Lung Cancer (IASLC). This work was supported in part by the Deutsche Krebshilfe through a Mildred-Scheel Fellowship to RK Thomas. T Shimamura holds a Career Development Award, as part of the Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence in Lung Cancer, NIH grant P20 CA90578.

Author information

Author notes

  1. Y Minami, T Shimamura and K Shah: These three authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Y Minami, T Shimamura, K Shah, T LaFramboise, K A Glatt, E Liniker, C L Borgman, H J Haringsma, W Feng, B A Weir, A M Lowell, J C Lee, G I Shapiro, K-K Wong, M Meyerson & R K Thomas

  2. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA, USA

    K Shah, T LaFramboise, W Feng, B A Weir, J C Lee, M Meyerson & R K Thomas

  3. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

    G I Shapiro & K-K Wong

  4. Department I for Internal Medicine, Center for Integrated Oncology, University of Cologne, Cologne, Germany

    J Wolf

  5. Department of Pathology, Harvard Medical School, Boston, MA, USA

    M Meyerson

  6. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    M Meyerson

  7. Max-Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max-Planck Society and the Medical Faculty of the University of Cologne, Cologne, Germany

    R K Thomas

  8. Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, Cologne, Germany

    R K Thomas

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Correspondence to M Meyerson or R K Thomas.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Minami, Y., Shimamura, T., Shah, K. et al. The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Oncogene 26, 5023–5027 (2007). https://doi.org/10.1038/sj.onc.1210292

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Keywords

  • lung cancer
  • targeted therapy
  • oncogene mutation
  • ERBB2
  • Her-2
  • kinase inhibitors

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