Preclinical Activity of the Rational Combination of Selumetinib (AZD6244) in Combination with Vorinostat in KRAS Mutant Colorectal Cancer Models
Menée in vitro et in vivo, cette étude évalue l'intérêt du selumetinib, un inhibiteur de MEK, en combinaison avec le vorinostat, un inhibiteur d'histone déacétylase, pour le traitement de patients atteints d'un cancer colorectal présentant des mutations du gène KRAS
Purpose:Despite the availability of several active regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor, supporting the development of novel approaches. In this study, we focused on the preclinical assessment of a rationally-based combination against KRAS mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a HDAC inhibitor. Experimental Design:Transcriptional profiling and gene set enrichment analysis of CRC cell lines provided the rationale for the combination. In vitro, the effects of this combination on tumor phenotype were assessed using monolayer and 3D cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, 18FDG-PET and 1H-NMR were performed to evaluate the growth inhibitory and metabolic responses in CRC xenografts. Results:In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G1, and reduced cellular migration. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed. Conclusions: These data indicate that the rationally-based combination of selumetinib with vorinostat, results in synergistic anti-proliferative activity against KRAS mutant CRC cell lines. In vivo, the combination demonstrated additive effects,associated with metabolic changes in phospholipid turnover, but not on FDG-PET, indicating that the former is a more sensitive endpoint of the combination effects.