FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3126366955> ?p ?o ?g. }

• W3126366955 endingPage "3200" @default.
• W3126366955 startingPage "3190" @default.
• W3126366955 abstract "Uveal melanoma is the most common eye cancer in adults. Approximately 50% of patients with uveal melanoma develop metastatic uveal melanoma (mUM) in the liver, even after successful treatment of the primary lesions. mUM is refractory to current chemo- and immune-therapies, and most mUM patients die within a year. Uveal melanoma is characterized by gain-of-function mutations in GNAQ/GNA11, encoding Gαq proteins. We have recently shown that the Gαq-oncogenic signaling circuitry involves a noncanonical pathway distinct from the classical activation of PLCβ and MEK-ERK. GNAQ promotes the activation of YAP1, a key oncogenic driver, through focal adhesion kinase (FAK), thereby identifying FAK as a druggable signaling hub downstream from GNAQ. However, targeted therapies often activate compensatory resistance mechanisms leading to cancer relapse and treatment failure.We performed a kinome-wide CRISPR-Cas9 sgRNA screen to identify synthetic lethal gene interactions that can be exploited therapeutically. Candidate adaptive resistance mechanisms were investigated by cotargeting strategies in uveal melanoma and mUM in vitro and in vivo experimental systems.sgRNAs targeting the PKC and MEK-ERK signaling pathways were significantly depleted after FAK inhibition, with ERK activation representing a predominant resistance mechanism. Pharmacologic inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in uveal melanoma cells and exerted cytotoxic effects, leading to tumor collapse in uveal melanoma xenograft and liver mUM models in vivo.Coupling the unique genetic landscape of uveal melanoma with the power of unbiased genetic screens, our studies reveal that FAK and MEK-ERK cotargeting may provide a new network-based precision therapeutic strategy for mUM treatment.See related commentary by Harbour, p. 2967." @default.
• W3126366955 created "2021-02-15" @default.
• W3126366955 creator A5002017233 @default.
• W3126366955 creator A5003822523 @default.
• W3126366955 creator A5006750757 @default.
• W3126366955 creator A5012410624 @default.
• W3126366955 creator A5012702025 @default.
• W3126366955 creator A5016616108 @default.
• W3126366955 creator A5016885261 @default.
• W3126366955 creator A5026067532 @default.
• W3126366955 creator A5026625543 @default.
• W3126366955 creator A5033733278 @default.
• W3126366955 creator A5038753309 @default.
• W3126366955 creator A5051883082 @default.
• W3126366955 creator A5053828591 @default.
• W3126366955 creator A5055703107 @default.
• W3126366955 creator A5062633858 @default.
• W3126366955 creator A5070873806 @default.
• W3126366955 creator A5073675187 @default.
• W3126366955 creator A5074055360 @default.
• W3126366955 date "2021-02-10" @default.
• W3126366955 modified "2023-10-15" @default.
• W3126366955 title "Synthetic Lethal Screens Reveal Cotargeting FAK and MEK as a Multimodal Precision Therapy for <i>GNAQ</i>-Driven Uveal Melanoma" @default.
• W3126366955 cites W1516077090 @default.
• W3126366955 cites W1969052506 @default.
• W3126366955 cites W1972760976 @default.
• W3126366955 cites W1988097700 @default.
• W3126366955 cites W1997335773 @default.
• W3126366955 cites W2025605951 @default.
• W3126366955 cites W2035922600 @default.
• W3126366955 cites W2038434969 @default.
• W3126366955 cites W2039939270 @default.
• W3126366955 cites W2053520756 @default.
• W3126366955 cites W2064297593 @default.
• W3126366955 cites W2072569544 @default.
• W3126366955 cites W2077517114 @default.
• W3126366955 cites W2077730236 @default.
• W3126366955 cites W2096439168 @default.
• W3126366955 cites W2099540110 @default.
• W3126366955 cites W2103557568 @default.
• W3126366955 cites W2103562758 @default.
• W3126366955 cites W2107060734 @default.
• W3126366955 cites W2109014958 @default.
• W3126366955 cites W2129420347 @default.
• W3126366955 cites W2144026118 @default.
• W3126366955 cites W2171564107 @default.
• W3126366955 cites W2172162633 @default.
• W3126366955 cites W2341757648 @default.
• W3126366955 cites W2401574182 @default.
• W3126366955 cites W2516337088 @default.
• W3126366955 cites W2613209365 @default.
• W3126366955 cites W2615656179 @default.
• W3126366955 cites W2762938139 @default.
• W3126366955 cites W2770300757 @default.
• W3126366955 cites W2793005533 @default.
• W3126366955 cites W2809699427 @default.
• W3126366955 cites W2904226822 @default.
• W3126366955 cites W2911710737 @default.
• W3126366955 cites W2915459742 @default.
• W3126366955 cites W2915951698 @default.
• W3126366955 cites W2922555277 @default.
• W3126366955 cites W2937925411 @default.
• W3126366955 cites W2948545594 @default.
• W3126366955 cites W2949451543 @default.
• W3126366955 cites W2952481429 @default.
• W3126366955 cites W2953090895 @default.
• W3126366955 cites W2955441129 @default.
• W3126366955 cites W3005387289 @default.
• W3126366955 cites W3011990562 @default.
• W3126366955 cites W3015906309 @default.
• W3126366955 cites W3083120491 @default.
• W3126366955 doi "https://doi.org/10.1158/1078-0432.ccr-20-3363" @default.
• W3126366955 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34389658" @default.
• W3126366955 hasPublicationYear "2021" @default.
• W3126366955 type Work @default.
• W3126366955 sameAs 3126366955 @default.
• W3126366955 citedByCount "31" @default.
• W3126366955 countsByYear W31263669552021 @default.
• W3126366955 countsByYear W31263669552022 @default.
• W3126366955 countsByYear W31263669552023 @default.
• W3126366955 crossrefType "journal-article" @default.
• W3126366955 hasAuthorship W3126366955A5002017233 @default.
• W3126366955 hasAuthorship W3126366955A5003822523 @default.
• W3126366955 hasAuthorship W3126366955A5006750757 @default.
• W3126366955 hasAuthorship W3126366955A5012410624 @default.
• W3126366955 hasAuthorship W3126366955A5012702025 @default.
• W3126366955 hasAuthorship W3126366955A5016616108 @default.
• W3126366955 hasAuthorship W3126366955A5016885261 @default.
• W3126366955 hasAuthorship W3126366955A5026067532 @default.
• W3126366955 hasAuthorship W3126366955A5026625543 @default.
• W3126366955 hasAuthorship W3126366955A5033733278 @default.
• W3126366955 hasAuthorship W3126366955A5038753309 @default.
• W3126366955 hasAuthorship W3126366955A5051883082 @default.
• W3126366955 hasAuthorship W3126366955A5053828591 @default.
• W3126366955 hasAuthorship W3126366955A5055703107 @default.
• W3126366955 hasAuthorship W3126366955A5062633858 @default.
• W3126366955 hasAuthorship W3126366955A5070873806 @default.
• W3126366955 hasAuthorship W3126366955A5073675187 @default.

• next