We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.
- Authors
Codony-Servat, Jordi; Cuatrecasas, Miriam; Asensio, Elena; Montironi, Carla; Martínez-Cardús, Anna; Marín-Aguilera, Mercedes; Horndler, Carlos; Martínez-Balibrea, Eva; Rubini, Michele; Jares, Pedro; Reig, Oscar; Victoria, Iván; Gaba, Lydia; Martín-Richard, Marta; Alonso, Vicente; Escudero, Pilar; Fernández-Martos, Carlos; Feliu, Jaime; Méndez, Jose Carlos; Méndez, Miguel
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.
- Subjects
ANTINEOPLASTIC agents; BIOLOGICAL transport; CAMPTOTHECIN; CELL nuclei; CELL physiology; CELLS; CELLULAR signal transduction; DRUG therapy; COLON tumors; DRUG resistance in cancer cells; FLUOROURACIL; FOLINIC acid; GENES; HETEROCYCLIC compounds; MOLECULAR chaperones; MONOCLONAL antibodies; ORGANOPLATINUM compounds; PROTEINS; RECTUM tumors; TRANSFERASES; UNSATURATED fatty acids; UREA; VITAMIN B complex; CURCUMIN; PHARMACODYNAMICS
- Publication
British Journal of Cancer, 2017, Vol 117, Issue 12, p1777
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/bjc.2017.279