Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma

Authors

  • Amandine Hurbin,

    Corresponding author
    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    • INSERM U823, Institut Albert Bonniot, BP170 Grenoble, F-38042 Cedex 9, France.
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  • Marie Wislez,

    1. ER2, Université Pierre et Marie Curie, Paris VI, France
    2. AP-HP Hôpital Tenon, Service Pneumologie et Réanimation, Paris, France
    3. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France
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  • Benoît Busser,

    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    3. Département Biochimie, Pharmacologie et Toxicologie, CHU Grenoble, France
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  • Martine Antoine,

    1. ER2, Université Pierre et Marie Curie, Paris VI, France
    2. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France
    3. AP-HP Hôpital Tenon, Service d'Anatomie Pathologique, Paris, France
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    • IFCT0401 expert pathologist.

  • Corine Tenaud,

    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    3. Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, France
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  • Nathalie Rabbe,

    1. ER2, Université Pierre et Marie Curie, Paris VI, France
    2. AP-HP Hôpital Tenon, Service Pneumologie et Réanimation, Paris, France
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  • Sandrine Dufort,

    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    3. Département Biochimie, Pharmacologie et Toxicologie, CHU Grenoble, France
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  • Florence de Fraipont,

    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    3. Département Biochimie, Pharmacologie et Toxicologie, CHU Grenoble, France
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  • Denis Moro-Sibilot,

    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    3. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France
    4. Pôle Médecine Aigüe Communautaire Pneumologie, CHU Grenoble, France
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  • Jacques Cadranel,

    1. ER2, Université Pierre et Marie Curie, Paris VI, France
    2. AP-HP Hôpital Tenon, Service Pneumologie et Réanimation, Paris, France
    3. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France
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    • IFCT0401 principal investigator.

  • Jean-Luc Coll,

    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
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  • Elisabeth Brambilla

    1. INSERM U823, Grenoble, France
    2. Université Joseph Fourier, Grenoble, France
    3. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France
    4. Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, France
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  • No conflicts of interest were declared.

Abstract

The appropriate selection of patients is a major challenge in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Prospective trials in adenocarcinoma demonstrated that the mucinous subtype presents a poorer outcome under EGFR-TKI treatment than the non-mucinous subtype. Our aim was to determine the molecular characteristics associated with resistance to EGFR-TKIs in mucinous and non-mucinous adenocarcinoma. Eighty adenocarcinoma samples, including 34 tumours from patients treated with gefitinib in a phase II clinical trial (IFCT0401), were classified as mucinous (n = 32) or non-mucinous (n = 48) adenocarcinoma. We demonstrated that four biological markers were differentially expressed between the two subtypes: mucinous tumours that overexpressed IGF1R (p < 0.0001) and amphiregulin (p = 0.004) with a tendency for more frequent KRAS mutations, in contrast to non-mucinous tumours that overexpressed EGFR (p < 0.0001) and TTF-1 (p < 0.0001) with more frequent EGFR mutations (p = 0.037). Higher IGF1R (p = 0.02) and lower TTF-1 (p = 0.02) expression was associated with disease progression under gefitinib treatment. We observed in vitro cross-talk between EGFR and IGF1R signalling pathways in gefitinib-resistant H358 mucinous cells. Anti-amphiregulin siRNAs and anti-IGF1R treatments sensitized the H358 cells to gefitinib-induced apoptosis with additive effects, suggesting that these treatments could overcome the resistance of mucinous tumours to EGFR-TKIs, including those with KRAS mutation. Our results highlighted that mucinous and non-mucinous adenocarcinoma subtypes are different entities with different therapeutic responses to EGFR-TKIs. These data will foster the development of therapeutic strategies for treating adenocarcinoma with mucinous component. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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