FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2981993825> ?p ?o ?g. }

• W2981993825 endingPage "104" @default.
• W2981993825 startingPage "91" @default.
• W2981993825 abstract "Abstract Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ataxia telangiectasia and rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. Notably, a number of different cancers, including Ewing sarcoma tumors, are sensitive to the combination of RNR and ATR-CHK1 inhibitors. However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single agents and in combination with RNR inhibitors, toward cancer cells. Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR–CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome. Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. Moreover, we show that the concurrent inhibition of ATR and WEE1 has a synergistic effect in Ewing sarcoma cells. Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors. Implications: Targeting the ATR, CHK1, and WEE1 kinases in Ewing sarcoma cells activates CDK2 and increases DNA replication stress by promoting the proteasome-mediated degradation of RRM2." @default.
• W2981993825 created "2019-11-01" @default.
• W2981993825 creator A5017927622 @default.
• W2981993825 creator A5024370810 @default.
• W2981993825 creator A5048993280 @default.
• W2981993825 creator A5076676733 @default.
• W2981993825 date "2020-01-01" @default.
• W2981993825 modified "2023-10-03" @default.
• W2981993825 title "Inhibition of the ATR–CHK1 Pathway in Ewing Sarcoma Cells Causes DNA Damage and Apoptosis via the CDK2-Mediated Degradation of RRM2" @default.
• W2981993825 cites W1181418255 @default.
• W2981993825 cites W1594035260 @default.
• W2981993825 cites W1628408467 @default.
• W2981993825 cites W1855851918 @default.
• W2981993825 cites W1878186877 @default.
• W2981993825 cites W1972623885 @default.
• W2981993825 cites W1973109316 @default.
• W2981993825 cites W1974861105 @default.
• W2981993825 cites W2010201645 @default.
• W2981993825 cites W2025679668 @default.
• W2981993825 cites W2028703908 @default.
• W2981993825 cites W2048069174 @default.
• W2981993825 cites W2050203263 @default.
• W2981993825 cites W2057272791 @default.
• W2981993825 cites W2062165702 @default.
• W2981993825 cites W2065942206 @default.
• W2981993825 cites W2073031672 @default.
• W2981993825 cites W2085305642 @default.
• W2981993825 cites W2086255242 @default.
• W2981993825 cites W2088256306 @default.
• W2981993825 cites W2098457059 @default.
• W2981993825 cites W2109125373 @default.
• W2981993825 cites W2121155221 @default.
• W2981993825 cites W2132089894 @default.
• W2981993825 cites W2135129680 @default.
• W2981993825 cites W2137271315 @default.
• W2981993825 cites W2142393970 @default.
• W2981993825 cites W2150755837 @default.
• W2981993825 cites W2155487282 @default.
• W2981993825 cites W2160600937 @default.
• W2981993825 cites W2164559547 @default.
• W2981993825 cites W2181205541 @default.
• W2981993825 cites W2209936495 @default.
• W2981993825 cites W2235521964 @default.
• W2981993825 cites W2331194212 @default.
• W2981993825 cites W2470708296 @default.
• W2981993825 cites W2513016538 @default.
• W2981993825 cites W2514410552 @default.
• W2981993825 cites W2546458004 @default.
• W2981993825 cites W2547198092 @default.
• W2981993825 cites W2567255685 @default.
• W2981993825 cites W2580528874 @default.
• W2981993825 cites W2592185869 @default.
• W2981993825 cites W2605336808 @default.
• W2981993825 cites W2609630616 @default.
• W2981993825 cites W2729989042 @default.
• W2981993825 cites W2745330422 @default.
• W2981993825 cites W2745704757 @default.
• W2981993825 cites W2767590922 @default.
• W2981993825 cites W2768190684 @default.
• W2981993825 cites W2770128744 @default.
• W2981993825 cites W2772130247 @default.
• W2981993825 cites W2792813139 @default.
• W2981993825 cites W2801282015 @default.
• W2981993825 cites W2888068269 @default.
• W2981993825 cites W2891992691 @default.
• W2981993825 cites W2895030469 @default.
• W2981993825 cites W2904649831 @default.
• W2981993825 cites W2904856500 @default.
• W2981993825 cites W2905875418 @default.
• W2981993825 cites W2911163118 @default.
• W2981993825 cites W2930487945 @default.
• W2981993825 cites W2937737908 @default.
• W2981993825 cites W4211227438 @default.
• W2981993825 doi "https://doi.org/10.1158/1541-7786.mcr-19-0585" @default.
• W2981993825 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6942212" @default.
• W2981993825 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31649026" @default.
• W2981993825 hasPublicationYear "2020" @default.
• W2981993825 type Work @default.
• W2981993825 sameAs 2981993825 @default.
• W2981993825 citedByCount "42" @default.
• W2981993825 countsByYear W29819938252020 @default.
• W2981993825 countsByYear W29819938252021 @default.
• W2981993825 countsByYear W29819938252022 @default.
• W2981993825 countsByYear W29819938252023 @default.
• W2981993825 crossrefType "journal-article" @default.
• W2981993825 hasAuthorship W2981993825A5017927622 @default.
• W2981993825 hasAuthorship W2981993825A5024370810 @default.
• W2981993825 hasAuthorship W2981993825A5048993280 @default.
• W2981993825 hasAuthorship W2981993825A5076676733 @default.
• W2981993825 hasBestOaLocation W29819938251 @default.
• W2981993825 hasConcept C104292427 @default.
• W2981993825 hasConcept C104317684 @default.
• W2981993825 hasConcept C105696609 @default.
• W2981993825 hasConcept C120504264 @default.
• W2981993825 hasConcept C134935766 @default.
• W2981993825 hasConcept C143425029 @default.
• W2981993825 hasConcept C147897179 @default.
• W2981993825 hasConcept C184235292 @default.

• next