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| Home > Articles > Published articles > Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer |
| Home > Articles > Published articles > Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer |
(Hospital Clínic i Provincial de Barcelona) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Hospital Clínic i Provincial de Barcelona) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Centro de Investigación Biomédica en Red de Cáncer) (Fundacion Jimenez Diaz) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia) (Institut d'Investigacions Biomèdiques August Pi i Sunyer)| Date: | 2017 |
| Abstract: | Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance. |
| Grants: | Instituto de Salud Carlos III PI13/01728 Instituto de Salud Carlos III CP13/00160 Instituto de Salud Carlos III PI14/00783 European Commission COLONGEVA Agència de Gestió d'Ajuts Universitaris i de Recerca 2014-SGR-0903 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014-SGR-135 |
| Note: | Altres ajuts: Mutua Madrileña (AP75002010); Porgrama CERCA; CIBERehd |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra, i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | IGF-1R ; Nuclear internalisation ; Acquired resistance ; Colorectal cancer ; BRAF mutation |
| Published in: | British Journal of Cancer, Vol. 117 (november 2017) , p. 1777-1786, ISSN 1532-1827 |
