TY - JOUR
T1 - Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer
AU - Codony-Servat, Jordi
AU - Cuatrecasas, Miriam
AU - Asensio, Elena
AU - Montironi, Carla
AU - Martínez-Cardús, Anna
AU - Marín-Aguilera, Mercedes
AU - Horndler, Carlos
AU - Martínez-Balibrea, Eva
AU - Rubini, Michele
AU - Jares, Pedro
AU - Reig, Oscar
AU - Victoria, Iván
AU - Gaba, Lydia
AU - Martín-Richard, Marta
AU - Alonso, Vicente
AU - Escudero, Pilar
AU - Fernández-Martos, Carlos
AU - Feliu, Jaime
AU - Méndez, Jose Carlos
AU - Méndez, Miguel
AU - Gallego, Javier
AU - Salud, Antonieta
AU - Rojo, Federico
AU - Castells, Antoni
AU - Prat, Aleix
AU - Rosell, Rafael
AU - García-Albéniz, Xabier
AU - Camps, Jordi
AU - Maurel, Joan
PY - 2017/1/1
Y1 - 2017/1/1
N2 - © 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.
AB - © 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.
KW - Acquired resistance
KW - BRAF mutation
KW - Colorectal cancer
KW - IGF-1R
KW - Nuclear internalisation
U2 - 10.1038/bjc.2017.279
DO - 10.1038/bjc.2017.279
M3 - Article
VL - 117
SP - 1777
EP - 1786
IS - 12
ER -