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Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma.: IGF1R inhibition in mucinous lung adenocarcinoma

Amandine Hurbin 1 Marie Wislez 2, 3, 4 Benoît Busser 5 Martine Antoine 2, 4, 6 Corine Tenaud 7, 8 Nathalie Rabbe 2, 3 Sandrine Dufort 7, 9 Florence de Fraipont 5 Denis Moro-Sibilot 7, 4, 10 Jacques Cadranel 2, 3, 4 Jean-Luc Coll 1 Elisabeth Brambilla 11
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.
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Submitted on : Monday, June 6, 2011 - 2:57:22 PM
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Amandine Hurbin, Marie Wislez, Benoît Busser, Martine Antoine, Corine Tenaud, et al.. Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma.: IGF1R inhibition in mucinous lung adenocarcinoma. Journal of Pathology, Wiley, 2011, 225 (1), pp.83-95. ⟨10.1002/path.2897⟩. ⟨inserm-00598462⟩



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