FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2896956819> ?p ?o ?g. }

• W2896956819 endingPage "e227" @default.
• W2896956819 startingPage "e226" @default.
• W2896956819 abstract "Glioblastoma (GBM) is the most common primary brain tumor in adults. Current treatment of GBM includes maximal resection followed by concurrent temozolomide (TMZ) and radiation therapy (RT). TMZ is an alkylating agent that methylates guanine bases at the O6 position (O6meG). O6meG-DNA methyltransferase (MGMT) repairs TMZ-induced DNA damage by removing these alkyl adducts. The promoter region of MGMT contains CpG islands that are methylated in approximately 45% of glioblastoma cases. Patients with a methylated MGMT promoter respond more readily to TMZ and survive 9 months longer than patients with an unmethylated MGMT promoter. Despite this prognostic benefit, these patients still have a median survival of only 22 months. The purpose of this study is two-fold: 1) to better understand the DNA damage response pathways that are activated in MGMT-methylated glioma cells upon treatment with alkylating agents, and 2) to determine if inhibiting these activated pathways sensitizes the glioma cells to alkylation damage, with or without ionizing radiation (IR). Our methods include comet assays, immunofluorescent imaging of DNA damage foci, western blotting, clonogenic survival assays, growth delay, flow cytometry, and mouse xenograft studies. Our assays were performed on a collection of human GBM cell lines engineered to express MGMT or not, including LN229 and U87 cells. Using comet assays and DNA damage foci, we showed that TMZ induces DNA double strand breaks (DSBs) in MGMT-methylated cells. These DSBs correspond temporally with cell cycle arrest in the S, G2, and M phases, as quantified by high-content microscopy and flow cytometry. We demonstrated that TMZ activates markers of replication stress in MGMT-methylated cells, specifically pChk1 S345 and pRPA32 S33. As these proteins are markers of ATR activation, we hypothesized that inhibition of ATR would sensitize MGMT-methylated cells to TMZ. This hypothesis was verified through clonogenic survival assays and growth delay assays; ATR inhibitors increase sensitivity to TMZ by over 100-fold in MGMT-methylated cells, but not in MGMT-expressing cells. Further exploration of the mechanism suggests that ATR inhibition with TMZ abrogates the normal cell cycle checkpoint that prevents replication with alkylated DNA, allowing cells to undergo replication catastrophe. Because we also showed that TMZ sensitizes MGMT-methylated cells to IR, our work suggests that the combination of ATR inhibition, TMZ and IR may further increase the therapeutic index over MGMT-expressing cells. Here, we report exquisite synergistic interactions between TMZ and inhibitors of a key DNA damage response protein, ATR. These interactions depend on MGMT status. These data lay the foundation for future clinical trials testing this combination in MGMT-methylated glioma. Since ATR inhibitors are radiosensitizers, we believed that this “triple combination” will be highly synergistic in the treatment of GBM." @default.
• W2896956819 created "2018-10-26" @default.
• W2896956819 creator A5040738951 @default.
• W2896956819 creator A5042139580 @default.
• W2896956819 creator A5066124700 @default.
• W2896956819 date "2018-11-01" @default.
• W2896956819 modified "2023-09-27" @default.
• W2896956819 title "Elucidation of an Exquisite Synergistic Interaction Between ATR Inhibitors and Alkylating Agents in MGMT-Methylated Glioma Cells" @default.
• W2896956819 doi "https://doi.org/10.1016/j.ijrobp.2018.07.774" @default.
• W2896956819 hasPublicationYear "2018" @default.
• W2896956819 type Work @default.
• W2896956819 sameAs 2896956819 @default.
• W2896956819 citedByCount "0" @default.
• W2896956819 crossrefType "journal-article" @default.
• W2896956819 hasAuthorship W2896956819A5040738951 @default.
• W2896956819 hasAuthorship W2896956819A5042139580 @default.
• W2896956819 hasAuthorship W2896956819A5066124700 @default.
• W2896956819 hasConcept C117262875 @default.
• W2896956819 hasConcept C134935766 @default.
• W2896956819 hasConcept C143425029 @default.
• W2896956819 hasConcept C1491633281 @default.
• W2896956819 hasConcept C153911025 @default.
• W2896956819 hasConcept C2777389519 @default.
• W2896956819 hasConcept C2778227246 @default.
• W2896956819 hasConcept C2780358455 @default.
• W2896956819 hasConcept C29537977 @default.
• W2896956819 hasConcept C33288867 @default.
• W2896956819 hasConcept C502942594 @default.
• W2896956819 hasConcept C552990157 @default.
• W2896956819 hasConcept C553184892 @default.
• W2896956819 hasConcept C55493867 @default.
• W2896956819 hasConcept C71924100 @default.
• W2896956819 hasConcept C86803240 @default.
• W2896956819 hasConcept C91965660 @default.
• W2896956819 hasConceptScore W2896956819C117262875 @default.
• W2896956819 hasConceptScore W2896956819C134935766 @default.
• W2896956819 hasConceptScore W2896956819C143425029 @default.
• W2896956819 hasConceptScore W2896956819C1491633281 @default.
• W2896956819 hasConceptScore W2896956819C153911025 @default.
• W2896956819 hasConceptScore W2896956819C2777389519 @default.
• W2896956819 hasConceptScore W2896956819C2778227246 @default.
• W2896956819 hasConceptScore W2896956819C2780358455 @default.
• W2896956819 hasConceptScore W2896956819C29537977 @default.
• W2896956819 hasConceptScore W2896956819C33288867 @default.
• W2896956819 hasConceptScore W2896956819C502942594 @default.
• W2896956819 hasConceptScore W2896956819C552990157 @default.
• W2896956819 hasConceptScore W2896956819C553184892 @default.
• W2896956819 hasConceptScore W2896956819C55493867 @default.
• W2896956819 hasConceptScore W2896956819C71924100 @default.
• W2896956819 hasConceptScore W2896956819C86803240 @default.
• W2896956819 hasConceptScore W2896956819C91965660 @default.
• W2896956819 hasIssue "3" @default.
• W2896956819 hasLocation W28969568191 @default.
• W2896956819 hasOpenAccess W2896956819 @default.
• W2896956819 hasPrimaryLocation W28969568191 @default.
• W2896956819 hasRelatedWork W1949057167 @default.
• W2896956819 hasRelatedWork W1961425141 @default.
• W2896956819 hasRelatedWork W1968601707 @default.
• W2896956819 hasRelatedWork W1981078074 @default.
• W2896956819 hasRelatedWork W2060647588 @default.
• W2896956819 hasRelatedWork W2067890744 @default.
• W2896956819 hasRelatedWork W2123730023 @default.
• W2896956819 hasRelatedWork W2514738721 @default.
• W2896956819 hasRelatedWork W2744631849 @default.
• W2896956819 hasRelatedWork W3170443625 @default.
• W2896956819 hasVolume "102" @default.
• W2896956819 isParatext "false" @default.
• W2896956819 isRetracted "false" @default.
• W2896956819 magId "2896956819" @default.
• W2896956819 workType "article" @default.