Molecular characterization of temsirolimus-induced response in human renal and bladder cancer cell lines.

Abstract

295 Background: Targeted therapies like mTOR inhibition is a clinically esthablished treatment modality for advanced renal cell cancer (RCC). We hypothesize that common elements of molecular signalling exists in RCC and transitional cell carcinoma of the bladder (TCC) that could provide a rational of the usage of this novel compound in human TCC. Therefore the goal of this investigation was to measure the in vivo and in vitro effect of temsirolimus/CCI-779 on human RCC and TCC cell lines on the molecular level. Methods: For in vivo experiments 3 RCC (786-O, A498, ACHN) cell lines and 7 TCC (T24, 5637, RT112, EJ-28, CLS-439, HB-CLS-1, HB-CLS-2) cell lines were compared. Effect of temsirolimus/CCI-779 was measured by real time impedance analysis (XCelligence, Roche). Following mRNA isolation microarray based mRNA expression analysis with 45.015 oligoprobes (G4112F, Agilent Technologies) was performed for molecular comparison of RCC and TCC cell lines. Expression patterns of 15 pathways were analyzed using the statistical software R (2.12.0) and the LIMMA package. Results: RCC and TCC cell lines demonstrated dose dependent inhibition of cellular growth with IC50 values of 10-20nM of temsirolimus/CCI-779 as measured by quantitative real time impedance analysis. Furthermore six out of 15 pathways including the mTOR and VEGF signalling were found with similar expression patterns following treatment with CCI-779 in both tumor entities. Conclusions: In vivo and in vitro analysis of temsirolimus mTOR inhitibtion on human bladder cancer cell lines support the hypothesis that a common molecular architectur exists in both tumor entities suggesting inhibition of mTOR in TCC as a possible target for further experimental therapeutic studies.