| Títol: | Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer |
|---|---|
| Autor/a: | 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; Gallego, Javier; Salud, Antonieta; Rojo, Federico; Castells, Antoni; Prat, Aleix; Rosell, Rafael; García-Albéniz, Xabier; Camps, Jordi; Maurel, Joan; Universitat Autònoma de Barcelona |
| Abstract: | Altres ajuts: Mutua Madrileña (AP75002010); Porgrama CERCA; CIBERehd |
| Abstract: | 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. 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. 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. Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance. |
| Matèries: | -IGF-1R -Nuclear internalisation -Acquired resistance -Colorectal cancer -BRAF mutation |
| Drets: | open access
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| Tipus de document: | Article |
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| Uri: | https://ddd.uab.cat/record/200564 |
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