MGMT-unmethylated glioblastoma [Neurosurgery Wiki]

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====== MGMT-unmethylated glioblastoma ======

In a subset of [[glioblastoma]]s, the [[MGMT promoter]] is methylated, impairing the repair mechanism and conferring [[chemosensitivity]]. However, MGMT is overexpressed in 60 % of glioblastomas providing an inherent resistance to [[alkylating agent]]s and challenging the role of [[temozolomide]] in this population.
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Das et al. tested two novel drugs: [[INC280]] ([[Capmatinib]]: a highly selective [[c-Met]] [[receptor]] [[tyrosine kinase]]-RTK inhibitor) and [[LDK378]] ([[Ceritinib]]: a highly selective anaplastic lymphoma kinase-[[ALK inhibitor]]), aiming to overcome [[TMZ]] resistance in MGMT-unmethylated Glioblastoma cells in in vitro cell culture models. Treatments were examined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, caspase-3 assay and western blot analysis. Results obtained from our experiments demonstrated that preconditioning with INC280 and LDK378 drugs exhibit increased MMR protein expression, specifically MMR protein MLH1 (MutL Homolog 1) and MSH6 (MutS Homolog 6) and sensitized TMZ in MGMT-unmethylated Glioblastoma cells via suppression of ALK and c-Met expression. INC280 and LDK378 plus TMZ also induced apoptosis by modulating downstream signaling of PI3K/AKT/STAT3. Taken together, this data indicates that co-inhibition of ALK and c-MET can enhance growth inhibitory effects in MGMT-unmethylated cells and enhance TMZ sensitivity in-vitro, suggesting [[c-Met inhibitor]]s combined with ALK-targeting provide a therapeutic benefit in MGMT-unmethylated Glioblastoma patients
((Das A, Alshareef M, Porto GBF, Infinger LK, Vandergrift WA 3rd, Lindhorst SM, Varma AK, Patel SJ, Cachia D. Preconditioning with [[INC280]] and [[LDK378]] drugs sensitizes [[MGMT-unmethylated glioblastoma]] to temozolomide: Pre-clinical assessment. J Neurol Sci. 2020 Nov 15;418:117102. doi: 10.1016/j.jns.2020.117102. Epub 2020 Aug 21. PMID: 32866816.))