Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma. - Archive ouverte HAL Access content directly
Journal Articles Journal of Pathology Year : 2011

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

(1) , (2, 3, 4) , (5) , (2, 4, 6) , (7, 8) , (2, 3) , (7, 9) , (5) , (7, 4, 10) , (2, 3, 4) , (1) , (11)
1
2
3
4
5
6
7
8
9
10
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.
Embargoed file
Embargoed file
Ne sera jamais visible
Loading...

Dates and versions

inserm-00598462 , version 1 (06-06-2011)

Identifiers

Cite

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, 2011, 225 (1), pp.83-95. ⟨10.1002/path.2897⟩. ⟨inserm-00598462⟩
115 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More