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Research Article

Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants

  • Heidi Greulich mail,

    To whom correspondence should be addressed. E-mail: heidig@broad.mit.edu (HG); E-mail: William_Sellers@dfci.harvard.edu (WRS); E-mail: Matthew_Meyerson@dfci.harvard.edu (MM)

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America

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  • Tzu-Hsiu Chen,

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America

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  • Whei Feng,

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America

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  • Pasi A Jänne,

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

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  • James V Alvarez,

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

    X
  • Mauro Zappaterra,

    Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America

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  • Sara E Bulmer,

    Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America

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  • David A Frank,

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

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  • William C Hahn,

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America, Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America

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  • William R Sellers mail,

    To whom correspondence should be addressed. E-mail: heidig@broad.mit.edu (HG); E-mail: William_Sellers@dfci.harvard.edu (WRS); E-mail: Matthew_Meyerson@dfci.harvard.edu (MM)

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America

    X
  • Matthew Meyerson mail

    To whom correspondence should be addressed. E-mail: heidig@broad.mit.edu (HG); E-mail: William_Sellers@dfci.harvard.edu (WRS); E-mail: Matthew_Meyerson@dfci.harvard.edu (MM)

    Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America, Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America

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  • Published: October 04, 2005
  • DOI: 10.1371/journal.pmed.0020313

Reader Comments (1)

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The need to establish an optimal approach

Posted by plosmedicine on 30 Mar 2009 at 23:50 GMT

Author: 'Hisayuki' 'Shigematsu'
Position: Clinical Fellow
Institution: Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry
E-mail: h-shige@ba3.so-net.ne.jp
Additional Authors: Shinichi Toyooka, Makoto Suzuki
Submitted Date: February 15, 2006
Published Date: February 22, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The research article by Greulich et al. [1] demonstrates the significance of insertion mutation of EGFR (exon 20) in tumorigenesis and responsiveness to tyrosine kinase inhibitors (TKIs) in lung cancers. They demonstrated that EGFR mutants showed different sensitivity to TKIs depending on its types. Although several papers found that patients harboring the mutation of EGFR kinase domain are sensitive to TKIs such as gefitinib or erlotinib [2, 3], other reports described that the T790M mutation in exon 20 is associated with resistance to TKIs [4, 5]. Increasing information about the relationship between EGFR status including mutation and gene copy number and drug sensitivities make it complex to establish the optimal approach under TKIs treatment for patients with non-small cell lung cancer (NSCLC).

Previously, we reported HER2 mutational status as well as EGFR and KRAS in a large number of NSCLC [6]. In this study, we found 22 % of EGFR kinase domain mutations (149 out of 671) and 15 cases had insertion mutation in exon 20. Of interest, major types of mutations, deletion in exon 19 (68 out of 149) and L858R in exon 21(61 out of 149), which are activating and sensitive to TKIs, were significantly (P less than 0.001) common in female and in never smokers, but insertion mutations target no bias in gender (7 in male versus 8 in female: P = 0.28) and smoking status (7 in smoker versus 8 in never smoker: P = 0.19), though number is small. In addition to the result by Greulich et al., our data also suggests the possibility that the EGFR mutations may be different among their types in terms of their etiology. Unfortunately, we have no data of the response to TKIs in these patients with insertion mutation to date. Based on their in vitro results, 15 patients with insertion mutation may have no benefit from conventional TKIs even they have EGFR kinase domain mutations.

We should consider the exact type of mutations, "Sensitive" or "Resistant" mutations, prior to TKIs therapy. Further, the development and clinical applications of novel agents overcoming resistance should be required to establish more effective strategy of molecular targeted therapy.

References

[1] Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, et al. (2005) Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2: e313

[2] Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, et al. (2004) EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304: 1497-1500.

[3] Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129-2139.

[4] Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, et al. (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352: 786-792.

[5] Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, et al. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2: e73.

[6] Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, et al. (2005) Somatic mutations of the HER2 kinase domain in lung adenocarcinoma. Cancer Res 65:1642-1646.

Competing interests declared: I declare that I have no competing interests."