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

Codony-Servat, J. ; Cuatrecasas, M. ; Asensio, E. ; Montironi, C. ; Martinez-Cardus, A. ; Marin-Aguilera, M. ; Horndler, C. ; Martinez-Balibrea, E. ; Rubini, M. ; Jares, P. ; Reig, O. ; Victoria, I. ; Gaba, L. ; Martin-Richard, M. ; Alonso, V. ; Escudero, P. ; Fernandez-Martos, C. ; Feliu, J. ; Mendez, J.C. ; Mendez, M. ; Gallego, J. ; Salud, A. ; Rojo, F. ; Castells, A. ; Prat, A. ; Rosell, R. ; Garcia-Albeniz, X. ; Camps, J. ; Maurel, J.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/bjc.2017.279

Año: 2017

Publicado en: BRITISH JOURNAL OF CANCER 117, 12 (2017), 1777-1786
ISSN: 0007-0920

Factor impacto JCR: 5.922 (2017)

Categ. JCR: ONCOLOGY rank: 38 / 222 = 0.171 (2017) - Q1 - T1

Factor impacto SCIMAGO: 2.89 - Oncology (Q1) - Cancer Research (Q1)

Tipo y forma: Article (Published version)