Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI

Marie Guerard 1, 2 Thomas Robin 1, 2 Pascal Perron 1, 2 Anne-Sophie Hatat 1 Laurence David-Boudet 3 Laetitia Vanwonterghem 2 Benoît Busser 2, 3 Jean-Luc Coll 2 Sylvie Lantuejoul 3 Béatrice Eymin 1 Amandine Hurbin 2 Sylvie Gazzeri 1
1 Team "RNA splicing, cell signaling and response to therapies"
IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 Team "Cancer targets and experimental therapeutics"
IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
Abstract : Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xeno-grafts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-b1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer.
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Marie Guerard, Thomas Robin, Pascal Perron, Anne-Sophie Hatat, Laurence David-Boudet, et al.. Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI. Cancer Letters, Elsevier, 2018, 420, pp.146-155. ⟨10.1016/j.canlet.2018.01.080⟩. ⟨inserm-02337427⟩

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