Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer

Jordi Codony-Servat, Miriam Cuatrecasas, Elena Asensio, Carla Montironi, Anna Martínez-Cardús, Mercedes Marín-Aguilera, Carlos Horndler, Eva Martínez-Balibrea, Michele Rubini, Pedro Jares, Oscar Reig, Iván Victoria, Lydia Gaba, Marta Martín-Richard, Vicente Alonso, Pilar Escudero, Carlos Fernández-Martos, Jaime Feliu, Jose Carlos Méndez, Miguel MéndezJavier Gallego, Antonieta Salud, Federico Rojo, Antoni Castells, Aleix Prat, Rafael Rosell, Xabier García-Albéniz, Jordi Camps, Joan Maurel

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30 Citations (Scopus)

Abstract

© 2017 Cancer Research UK. All rights reserved. Background: 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. Methods: 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. Results: 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. Conclusions: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.
Original languageEnglish
Pages (from-to)1777-1786
JournalBritish Journal of Cancer
Volume117
Issue number12
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Acquired resistance
  • BRAF mutation
  • Colorectal cancer
  • IGF-1R
  • Nuclear internalisation

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