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

ABSTRACT: 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.

SUBMITTER: Codony-Servat J

PROVIDER: S-EPMC5729466 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Codony-Servat Jordi J Cuatrecasas Miriam M Asensio Elena E Montironi Carla C Martínez-Cardús Anna A Marín-Aguilera Mercedes M Horndler Carlos C Martínez-Balibrea Eva E Rubini Michele M Jares Pedro P Reig Oscar O Victoria Iván I Gaba Lydia L Martín-Richard Marta M Alonso Vicente V Escudero Pilar P Fernández-Martos Carlos C Feliu Jaime J Méndez Jose Carlos JC Méndez Miguel M Gallego Javier J Salud Antonieta A Rojo Federico F Castells Antoni A Prat Aleix A Rosell Rafael R García-Albéniz Xabier X Camps Jordi J Maurel Joan J

British journal of cancer 20171109 12

<h4>Background</h4>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.<h4>Methods</h4>We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-I ...[more]

PMID: 29123263

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Project description:BACKGROUND:Chemotherapy resistance is a great obstacle in effective treatment for metastatic triple negative breast cancer (TNBC). The ability to predict chemotherapy response would allow chemotherapy administration to be directed toward only those patients who would benefit, thus maximizing treatment efficiency. Differentially expressed plasma proteins may serve as putative biomarkers for predicting chemotherapy outcomes. PATIENTS AND METHODS:In this study, 26 plasma samples (10 samples with partial response (S) and 16 samples with progression disease (R)) from patients with metastatic TNBC were measured by Tandem Mass Tag (TMT)-based proteomics analysis to identify differentially expressed proteins between the S and R group. Potential proteinswere validated with enzyme-linked immunosorbent assay (ELISA) in another 67 plasma samples. RESULTS:A total of 320 plasma proteins were identified, and statistical analysis showed that 108 proteins were significantly dysregulated between R and S groups in the screening stage. Bioinformatics revealed relevant pathways and regulatory networks of the differentially expressed proteins. Three differentially expressed proteins were validated by ELISA with 67 samples from TNBC patients. The R group had significantly higher plasma CAMK2A level than the S group (P=0.0074). The ROC curve analysis showed an AUC of 0.708, with sensitivity 48.4% and specificity 86.1%. In multivariate logistic regression analysis, the level of plasma CAMK2A was also significant for chemotherapeutic response (P=0.009, OR=0.152). Furthermore, the patients with higher CAMK2A level had shorter OS than those with lower CAMK2A level, which amounted to 13.9 and 28.9 months, respectively (P=0.034). In the multivariate Cox regression analysis, CAMK2A level still had significant effect on OS (P=0.031, HR=1.865). CONCLUSION:TMT-based proteomic analysis was able to identify potential biomarkers in plasma that predicted chemotherapy resistance in the metastatic TNBC. The plasma of CAMK2A level may serve as apotential predictive and prognostic biomarker for chemotherapy in metastatic TNBC.

Dataset Information

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

Publications

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

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