Web of Science: 10 citations, Scopus: 10 citations, Google Scholar: citations,
Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer
Codony Servat, Jordi (Institut Germans Trias i Pujol. Institut Català d'Oncologia)
Cuatrecasas Freixas, Miriam
Asensio, Elena (Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
Montironi, Carla (Hospital Clínic)
Martínez Cardús, Anna (Institut Germans Trias i Pujol. Institut Català d'Oncologia)
Marín Aguilera, Mercedes (Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
Horndler, Carlos (Hospital Miguel Servet)
Martínez Balibrea, Eva (Institut Germans Trias i Pujol. Institut Català d'Oncologia)
Rubini, Michele (Department of Experimental and Diagnostic Medicine, University of Ferrara)
Jares, Pedro (Hospital Clínic)
Reig, Oscar (Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
Victoria, Iván (Medical Oncology Department, Hospital Clínic, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Universitat de Barcelona)
Gaba, Lydia (Medical Oncology Department, Hospital Clínic, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Universitat de Barcelona)
Martín Richard, Marta (Institut d'Investigació Biomèdica Sant Pau)
Alonso, Vicente (Hospital Miguel Servet)
Escudero, Pilar (Hospital Clínico Universitatio Lozano Blesa)
Fernández-Martos, Carlos (Instituto Valenciano de Oncología)
Feliu, Jaime (Hospital La Paz, CIBERONC)
Méndez, Jose Carlos (Centro Oncológico de Galicia)
Méndez, Miguel (Hospital de Móstoles)
Gallego, Javier (Hospital de Elche)
Salud, Antonieta (Hospital Arnau de Vilanova)
Rojo, Federico (Pathology Department, Fundación Jiménez Diaz University)
Castells, Antoni (Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
Prat, Aleix (Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
Rosell, Rafael (Institut Germans Trias i Pujol. Institut Català d'Oncologia)
García-Albéniz, Xabier (Harvard T.H. Chan School of Public Health)
Camps, Jordi (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia)
Maurel, Joan (Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

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.
Note: Altres ajuts: Mutua Madrileña (AP75002010); Porgrama CERCA; CIBERehd
Note: Número d'acord de subvenció ISCIII/PI13/01728
Note: Número d'acord de subvenció ISCIII/CP13/00160
Note: Número d'acord de subvenció ISCIII/PI14/00783
Note: Número d'acord de subvenció EU/COLONGEVA
Note: Número d'acord de subvenció AGAUR/2014 SGR 0903
Note: Número d'acord de subvenció AGAUR/2014 SGR 135
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 Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
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

DOI: 10.1038/bjc.2017.279
PMID: 29123263


10 p, 1.9 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut d'Investigació Biomèdica Sant Pau
Articles > Research articles
Articles > Published articles

 Record created 2018-12-24, last modified 2019-05-23



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