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Characterization of Glioblastoma Cells Response to Regorafenib

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Simple Summary Glioblastoma is the most aggressive primary brain tumor, characterized by a short survival and by an invariably poor outcome. The clinical management of glioblastoma patients is based on… Click to show full abstract

Simple Summary Glioblastoma is the most aggressive primary brain tumor, characterized by a short survival and by an invariably poor outcome. The clinical management of glioblastoma patients is based on surgery followed by adjuvant radio-chemotherapy. Glioblastoma therapy remained substantially unaltered in the last two decades, due to the lack of significant therapeutic alternatives. Regorafenib, a multikinase inhibitor already used as an anticancer drug for hepatocellular carcinoma, has recently been introduced as a therapy for relapsed glioblastoma, based on the encouraging results of a randomized phase II clinical trial. However, very little is known about the mechanisms governing glioblastoma cells’ response to regorafenib. Here we present an in vitro study, performed on glioblastoma tumor cells and on patient-derived glioma stem cells, aiming at characterizing the cellular response to regorafenib. Overall, the emerging message is that regorafenib limits glioblastoma cell proliferation, but might eventually increase the tumor cells’ migration ability. Abstract Glioblastoma (GBM), the most malignant primary brain tumor in adults. Although not frequent, it has a relevant social impact because the peak incidence coincides with the age of professional maturity. A number of novel treatments have been proposed, yet clinical trials have been disappointing. Recently, a phase II clinical trial (REGOMA) demonstrated that the multikinase inhibitor regorafenib significantly increased the median overall survival (OS) of GBM patients when compared to lomustine-treated patients. On this basis, the National Comprehensive Cancer Network (NCCN) 2020 Guidelines included regorafenib as a preferred regimen in relapsed GBM treatment. Despite the use in GBM patients’ therapy, little is known about the molecular mechanisms governing regorafenib effectiveness on the GBM tumor. Here we report an in vitro characterization of GBM tumor cells’ response to regorafenib, performed both on cell lines and on patient-derived glioma stem cells (GSCs). Overall, regorafenib significantly reduced cell growth of 2D tumor cell cultures and of 3D tumor spheroids. Strikingly, this effect was accompanied by transcriptional regulation of epithelial to mesenchymal transition (EMT) genes and by an increased ability of surviving tumor cells to invade the surrounding matrix. Taken together, our data suggest that regorafenib limits cell growth, however, it might induce an invasive phenotype.

Keywords: glioblastoma; response regorafenib; regorafenib; cells response; tumor

Journal Title: Cancers
Year Published: 2022

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