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., ... Maurel, J. (2017). Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer. British Journal of Cancer, 117(12), 1777-1786. https://doi.org/10.1038/bjc.2017.279
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.