In vitro chemosensitivity against enzastaurin correlates with gene expression of IL8 and GSK3-beta
13046 Background: Enzastaurin (E) is an active antitumoral agent which selectively inhibits the β-isoform of protein kinase C (PKC-β). The compound blocks the enzyme’s ATP-binding site and signal transmission is abrogated resulting in the inhibition of neovascularization. The aim of the present study was to correlate gene expression with in vitro chemosensitivity of freshly explanted human tumor specimens. Such correlations in tumors taken directly from patients will help to rationally design subsequent clinical trials. Methods: Soft-agar colony forming assays were performed on freshly biopsied tumor cells exposed to various concentrations of E. Corresponding pieces of tumor specimens were shock-frozen and prepared for RNA isolation and cDNA generation followed by multiplex real-time PCR experiments. Gene expression data were correlated against cloning assay results. Results: Gene expression data of PKC-β1, PKC-β2, IL8RA, IL8RB, IL8, GSK3-β, and TGF-β were correlated against in vitro chemosensitivity pattern of E from 66 samples. After 1h-drug exposure gene expressions in sensitive versus resistant specimens were statistically significant with p = 0.013 for IL8 [median copy number (mcn): 1881 vs. 694; n = 66] and p = 0.012 for GSK3-beta (mcn: 1.6 vs. 7.0; n = 66). No correlation was detected for PKC-β1, PKC-β2, IL8RA, and IL8RB. Detection of TGF-β failed in most samples. Conclusions: Low expression of GSK3-β and high expression of IL8 correlate statistically significantly with increased in vitro sensitivity to E in freshly explanted human tumors. These findings may help direct further clinical development of this compound. No significant financial relationships to disclose.