Journal Article

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

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

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/4028 / 692/4028/67 / 692/4028/67/1504 / 692/4028/67/1504/1885 / Aged / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - pharmacology / Antineoplastic Agents - pharmacology / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Bevacizumab - administration & dosage / Biomedical and Life Sciences / Biomedicine / Camptothecin - administration & dosage / Camptothecin - analogs & derivatives / Cancer Research / Cell Nucleus - metabolism / Cell Survival - drug effects / Cetuximab - administration & dosage / Chemoresistance / Chemotherapy / Clinical trials / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Curcumin - pharmacology / Dasatinib - pharmacology / Drug Resistance / Drug Resistance, Neoplasm / Epidemiology / Fatty Acids, Unsaturated - pharmacology / Female / Fluorouracil - administration & dosage / Fluorouracil - pharmacology / Gene Silencing / HCT116 Cells / HT29 Cells / Humans / Immunohistochemistry / Insulin / Insulin-like growth factor I / Insulin-like growth factors / Leucovorin - administration & dosage / Male / Metastases / Metastasis / Middle Aged / Molecular Chaperones - genetics / Molecular Chaperones - metabolism / Molecular Medicine / Molecular Targeted Therapy / Monoclonal antibodies / Niacinamide - analogs & derivatives / Niacinamide - pharmacology / Oncology / Organoplatinum Compounds - administration & dosage / Organoplatinum Compounds - pharmacology / Oxaliplatin / Panitumumab / Phenylurea Compounds - pharmacology / Protein Inhibitors of Activated STAT - genetics / Protein Inhibitors of Activated STAT - metabolism / Protein Transport - drug effects / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins p21(ras) - genetics / Pyrimidines - pharmacology / Pyrroles - pharmacology / Receptor, IGF Type 1 - metabolism / RNA-mediated interference / Signal Transduction - drug effects / Sorafenib / SUMO protein / Translational Therapeutics / Tumors