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Cancer Lett. 2018 Apr 28;420:146-155. doi: 10.1016/j.canlet.2018.01.080. Epub 2018 Feb 6.

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

Author information

1
Team "RNA splicing, cell signalling and response to therapies", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France; Team "Cancer targets and experimental therapeutics", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: guerard_marie@yahoo.fr.
2
Team "RNA splicing, cell signalling and response to therapies", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France; Team "Cancer targets and experimental therapeutics", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: robintho26@gmail.com.
3
Team "RNA splicing, cell signalling and response to therapies", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France; Team "Cancer targets and experimental therapeutics", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: pascal.perron@univ-grenoble-alpes.fr.
4
Team "RNA splicing, cell signalling and response to therapies", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: anne-sophie.hatat@univ-grenoble-alpes.fr.
5
Grenoble Univ. Hospital, 38000 Grenoble France. Electronic address: LDavid-boudet@chu-grenoble.fr.
6
Team "Cancer targets and experimental therapeutics", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: laetitia.vanwonterghem@univ-grenoble-alpes.fr.
7
Team "Cancer targets and experimental therapeutics", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France; Grenoble Univ. Hospital, 38000 Grenoble France. Electronic address: BBusser@chu-grenoble.fr.
8
Team "Cancer targets and experimental therapeutics", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: jean-luc.coll@univ-grenoble-alpes.fr.
9
Grenoble Univ. Hospital, 38000 Grenoble France. Electronic address: SLantuejoul@chu-grenoble.fr.
10
Team "RNA splicing, cell signalling and response to therapies", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: Beatrice.Eymin@univ-grenoble-alpes.fr.
11
Team "Cancer targets and experimental therapeutics", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: amandine.hurbin@inserm.fr.
12
Team "RNA splicing, cell signalling and response to therapies", Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France. Electronic address: Sylvie.Gazzeri@univ-grenoble-alpes.fr.

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 p21WAF1/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.

KEYWORDS:

EGFR-TKI; IGF1R; Lung cancer; Nuclear trafficking; Resistance

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