Time resolved amplified FRET identifies protein kinase B activation state as a marker for poor prognosis in clear cell renal cell carcinoma
| Autor: | Christopher J. Applebee, Pierre Leboucher, José I. López, Peter J. Parker, James Miles, Sonia Lopez-Fernandez, Rosa Guarch, Dae-Jin Lee, Banafshé Larijani, Stephen G. Ward |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Clear cell renal cell carcinoma Pathology medicine.medical_specialty PTEN clear cell renal cell carcinoma Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Breast cancer Physiology (medical) medicine Biomarker activation Protein kinase B PI3K/AKT/mTOR pathway breast-cancer Fret-FLIM AKT/PKB biology amplified fret Hazard ratio protein kinase b (pkb/akt) Regular Article medicine.disease Prognosis 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Molecular Medicine Immunohistochemistry prognosis fret-flim Amplified FRET Clear cell Protein kinase B (PKB/Akt) biomarker activation |
| Zdroj: | Miles, J, Applebee, C J, Leboucher, P, Lopez-Fernandez, S, Lee, D-J, Guarch, R, Ward, S, Parker, P J, López, J I & Larijani, B 2017, ' Time resolved amplified FRET identifies protein kinase B activation state as a marker for poor prognosis in clear cell renal cell carcinoma ', BBA Clinical, pp. 97-102 . https://doi.org/10.1016/j.bbacli.2017.10.002 BBA Clinical Addi. Archivo Digital para la Docencia y la Investigación instname |
| DOI: | 10.1016/j.bbacli.2017.10.002 |
| Popis: | Purpose Clear cell Renal Cell Carcinomas (ccRCC), the largest group of renal tumours, are resistant to classical therapies. The determination of the functional state of actionable biomarkers for the assessment of these adenocarcinomas is essential. The dysregulation of the oncoprotein, PKB/Akt has been linked with poor prognoses in human cancers. Material & methods We analysed the status of the PKB/Akt pathway in a representative tumour tissue microarray obtained from the primary tumours and their metastases in 60 ccRCC with long term follow up. We sought to define the evolution of this pathway from the primary tumour to the metastatic event and to know the impact of its functional state in tumour aggressiveness and patient survival. Two-site time resolved amplified FRET (A-FRET) was utilised for assessing the activation state of PKB/Akt and this was compared to conventional immunohistochemistry measurements. Results Activation state of PKB/Akt in primary tumours defined by A-FRET correlated with poorer overall survival (hazard ratio 0.228; p = 0.002). Whereas, increased protein expression of phosphoPKB/Akt, identified using classical immunohistochemistry, yielded no significant difference (hazard ratio 1.390; p = 0.548). Conclusions Quantitative determination of PKB/Akt activation in ccRCC primary tumours alongside other diagnostics tools could prove key in taking oncologists closer to an efficient personalised therapy in ccRCC patients. General significance The quantitative imaging technology based on Amplified-FRET can rapidly analyse protein activation states and molecular interactions. It could be used for prognosis and assess drug function during the early cycles of chemotherapy. It enables evaluation of clinical efficiency of personalised cancer treatment. Highlights • Time Resolved Amplified FRET (A-FRET), has been used to quantitatively assess PKB/Akt activation states in ccRCC. • Increased activation state of PKB/Akt in primary tumours was shown to correlate with poorer prognoses. • Companion diagnostic tools such as A-FRET will prove valuable for assessing prognostic models and for predicting the response to systemic therapy. |
| Databáze: | OpenAIRE |
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