Carbonic Anhydrase 9 Expression Increases with Vascular Endothelial Growth Factor-Targeted Therapy and Is Predictive of Outcome in Metastatic Clear Cell Renal Cancer

Grant D Stewart, Fiach C O'Mahony, Alexander Laird, Sukaina Rashid, Sarah A Martin, Lel Eory, Alexander L R Lubbock, Jyoti Nanda, Marie O'Donnell, Alan Mackay, Peter Mullen, S Alan McNeill, Antony C P Riddick, Michael Aitchison, Daniel Berney, Axel Bex, Ian M Overton, David J Harrison, Thomas Powles

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
179 Downloads (Pure)

Abstract

Background: There is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy. Objective: To explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome. Design, setting, and participants Multiple frozen samples from primary tumours were taken from sunitinib-naïve (n = 22) and sunitinib-treated mccRCC patients (n = 23) for protein analysis. A cohort (n = 86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings. Intervention Three cycles of sunitinib 50 mg (4 wk on, 2 wk off). Outcome measurements and statistical analysis Reverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression. Results and limitations: Differential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p < 0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural variance and significant differential expression with therapy. The validation cohort confirmed increased CA9 expression with therapy. Multivariate analysis showed high CA9 expression after treatment was associated with longer survival (hazard ratio: 0.48; 95% confidence interval, 0.26–0.87; p = 0.02). Array CGH profiles revealed sunitinib was associated with significant CA9 region loss. RNAi CA9 silencing in two cell lines inhibited the antiproliferative effects of sunitinib. Shortcomings of the study include selection of a specific protein for analysis, and the specific time points at which the treated tissue was analysed. Conclusions: CA9 levels increase with targeted therapy in mccRCC. Lower CA9 levels are associated with a poor prognosis and possible resistance, as indicated by the validation cohort. Patient summary: Drug treatment of advanced kidney cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy.
Original languageEnglish
Pages (from-to)956–963
Number of pages8
JournalEuropean Urology
Volume66
Issue number5
Early online date10 May 2014
DOIs
Publication statusPublished - Nov 2014

Bibliographical note

Medical Research Council funding (A. Laird, I.M. Overton)

Fingerprint

Dive into the research topics of 'Carbonic Anhydrase 9 Expression Increases with Vascular Endothelial Growth Factor-Targeted Therapy and Is Predictive of Outcome in Metastatic Clear Cell Renal Cancer'. Together they form a unique fingerprint.

Cite this