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

被引：70

作者：

Codony-Servat, Jordi ^{[1
,2
]}

Cuatrecasas, Miriam ^{[3
]}

Asensio, Elena ^{[4
]}

Montironi, Carla ^{[3
]}

Martinez-Cardus, Anna ^{[2
]}

Marin-Aguilera, Mercedes ^{[1
]}

Horndler, Carlos ^{[5
]}

Martinez-Balibrea, Eva ^{[2
]}

Rubini, Michele ^{[6
]}

Jares, Pedro ^{[3
]}

Reig, Oscar ^{[1
]}

Victoria, Ivan ^{[1
]}

Gaba, Lydia ^{[1
]}

Martin-Richard, Marta ^{[7
]}

Alonso, Vicente ^{[8
]}

Escudero, Pilar ^{[9
]}

Fernandez-Martos, Carlos ^{[10
]}

Feliu, Jaime ^{[11
]}

Mendez, Jose Carlos ^{[12
]}

Mendez, Miguel ^{[13
]}

Gallego, Javier ^{[14
]}

Salud, Antonieta ^{[15
]}

Rojo, Federico ^{[16
]}

Castells, Antoni ^{[4
]}

Prat, Aleix ^{[1
]}

Rosell, Rafael ^{[2
]}

Garcia-Albeniz, Xabier ^{[17
]}

Camps, Jordi ^{[4
,18
]}

Maurel, Joan ^{[1
]}

机构：

[1] Univ Barcelona, Hosp Clin, Med Oncol Dept,IDIBAPS, Translat Genom & Targeted Therapeut Solid Tumors, C Villarroel 170, Barcelona 08036, Spain

[2] Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Crta Canyet S-N, Badalona 08916, Spain

[3] Univ Barcelona, Pathol Dept, Hosp Clin & Tumour Bank Biobank, IDIBAPS, C Villarroel 170, Barcelona 08036, Spain

[4] IDIBAPS, CIBERehd, Gastrointestinal & Pancreat Oncol Grp, C Rossello 149-153, Barcelona 08036, Spain

[5] Hosp Miguel Servet, Pathol Serv, Paseo Isabel Catol 1-3, Zaragoza 50009, Spain

[6] Univ Ferrara, Dept Expt & Diagnost Med, Via Savonarola 9, I-44121 Ferrara, Italy

[7] Hosp Sant Pau, Dept Oncol, C Sant Quinti 89, Barcelona 08026, Spain

[8] Hosp Miguel Servet, Dept Oncol, Paseo Isabel Catol 1-3, Zaragoza 50009, Spain

[9] Univ Lozano Blesa, Hosp Clin, Dept Oncol, Av San Juan Bosco 15, Zaragoza 50009, Spain

[10] Inst Valenciano Oncol, Dept Med Oncol, C Prof Beltran Baguena 8, Valencia 46009, Spain

[11] CIBERONC, Hosp La Paz, Dept Oncol, Pso Castellana 261, Madrid 28046, Spain

[12] Ctr Oncol Galicia, Dept Oncol, C Doctor Camilo Veiras 1, La Coruna 15009, Spain

[13] Hosp Mostoles, Dept Oncol, Ri Jucar S-N, Mostoles 28935, Spain

[14] Hosp Elche, Dept Oncol, C Almazara 11, Elche 03203, Spain

[15] Hosp Arnau Vilanova, Dept Oncol, Av Alcalde Rovira Roure 80, Lleida 25198, Spain

[16] Fdn Jimenez Diaz Univ, Pathol Dept, Av Reyes Catol 2, Madrid 28040, Spain

[17] Harvard TH Chan Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA

[18] Univ Autonoma Barcelona, Dept Biol Cellular Fisiol & Immunol, Unitat Biol Cellular & Genet Med, E-08193 Barcelona, Spain

来源：

BRITISH JOURNAL OF CANCER | 2017年 / 117卷 / 12期

关键词：

IGF-1R; nuclear internalisation; acquired resistance; colorectal cancer; BRAF mutation; I RECEPTOR; TRANSCRIPTION FACTOR; MUTATION STATUS; POOR-PROGNOSIS; TUMOR-CELLS; INSULIN; COMBINATION; EXPRESSION; INHIBITOR; KRAS;

D O I：

10.1038/bjc.2017.279

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1777 / 1786

页数：10

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