Combined Inhibition of HER1/EGFR and RAC1 Results in a Synergistic Antiproliferative Effect on Established and Primary Cultured Human Glioblastoma Cells
Menée sur des lignées cellulaires, cette étude suggère que l'inhibition de RAC1 permettrait de renforcer l'activité antitumorale de l'erlotinib dans le traitement de patients atteints d'un glioblastome
Glioblastoma is the most frequent brain tumor of glial origin in adults. With the best available standard of care, patients with this disease have a life expectancy of only approximately 15 months after diagnosis. Since the epidermal growth factor receptor (HER1/EGFR) is one of the most commonly dysregulated oncogenes in glioblastoma, HER1/EGFR-targeted agents such as erlotinib were expected to provide a therapeutic benefit. However, their application in the clinical setting failed. Seeking an explanation for this finding, we previously identified several candidate genes for resistance of human glioblastoma cell lines towards erlotinib. Based on this panel of genes, we aimed at identifying drugs that synergistically enhance the antiproliferative effect of erlotinib on established and primary glioblastoma cell lines. We found that NSC23766, an inhibitor of RAC1, enhanced the antineoplastic effects of erlotinib in U87MG, T98MG and A172MG glioblastoma cell lines for the most part in a synergistic or at least in an additive manner. In addition, the synergistic antiproliferative effect of erlotinib and NSC23766 was confirmed in primary cultured cells, indicating a common underlying cellular and molecular mechanism in glioblastoma. Therefore, agents that suppress RAC1 activation may be useful therapeutic partners for erlotinib in a combined targeted treatment for glioblastoma.
http://mct.aacrjournals.org/content/early/2013/07/04/1535-7163.MCT-13-0052.abstract