Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI. (28th April 2018)

• Record Type: Journal Article
• Authors: Guerard, Marie; Robin, Thomas; Perron, Pascal; Hatat, Anne-Sophie; David-Boudet, Laurence; Vanwonterghem, Laetitia; Busser, Benoit; Coll, Jean-Luc; Lantuejoul, Sylvie; Eymin, Beatrice; Hurbin, Amandine; Gazzeri, Sylvie
• Is Part Of: Cancer letters. Volume 420(2018)
• Page Start: 146
• Page End: 155
• Publication Date: 2018-04-28
• Subjects: IGF1R -- Nuclear trafficking -- EGFR-TKI -- Resistance -- Lung cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.01.080
• Languages: English
• ISSNs: 0304-3835

Abstract

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 xenografts, 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-β1 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. Highlights: EGFR-TKI induces nuclear accumulation of IGF1R in mucinous lung adenocarcinoma. Nuclear accumulation of IGF1R by gefitinib requires intracellular amphiregulin. Amphiregulin enables IGF1R binding to importin-β1 and permits its nuclear transport. Nuclear IGF1R induces G1 arrest and promotes resistance to gefitinib.