FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4205908298> ?p ?o ?g. }

• W4205908298 endingPage "463" @default.
• W4205908298 startingPage "463" @default.
• W4205908298 abstract "463 Background: Molecularly targeted therapy is gaining traction in cholangiocarcinoma with the first FDA approval of a targeted agent in 2020, the FGFR inhibitor pemigatinib. Yet response rates and efficacy are modest, and most cholangiocarcinoma patients still lack targeted therapy options. The hippo pathway effector, YAP, is an oncogene that is activated in the majority of cholangiocarcinoma, yet attempts to develop YAP inhibitors have not yet been clinically successful. Recently, we described a novel mechanism of YAP regulation, via tyrosine phosphorylation by the Src-family kinase LCK. Therefore we hypothesized that LCK inhibition by may be therapeutic in cholangiocarcinoma through suppression of YAP activity. Methods: NTRC 0652-0 is a novel tyrosine kinase inhibitor with specificity for LCK. In vitro pharmacodynamics were defined. In cholangiocarcinoma cells, specificity for LCK inhibition was determined by mass spectrometry-based unbiased analysis of the tyrosine phosphoproteome following treatment with NTRC 0652-0 or genetic deletion of LCK. YAP phosphorylation and cotranscriptional activity, cell viability, and apoptosis were assessed. A panel of eight cholangiocarcinoma patient derived organoids (PDO) were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft (PDX) models bearing FGFR2-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. Results: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in cholangiocarcinoma cells. NTRC 0652-0 treatment led to YAP inhibition and apoptotic cell death in cholangiocarcinoma cell lines, associated with inhibition of MCL1 expression. PDOs demonstrated variable sensitivity to NTRC 0652-0, correlated with basal YAP tyrosine phosphorylation and drug-induced suppression of YAP co-transcriptional activity. FGFR2-altered cholangiocarcinoma was also identified as a subset with enrichment of YAP target genes. Cells from an FGFR2-altered PDX were sensitive to NTRC 0652-0 despite being primarily resistant to pemigatinib. In two PDX models of FGFR2-altered cholangiocarcinoma, daily oral treatment with NTRC 0652-0 inhibited YAP tyrosine phosphorylation, and resulted in stable plasma and tumor drug levels, acceptable toxicity, and significantly decreased tumor growth. Conclusions: A novel LCK inhibitor, NTRC 0652-0, reduced YAP signaling and demonstrated preclinical efficacy in multiple patient-derived models of cholangiocarcinoma. LCK is a novel therapeutic target in cholangiocarcinoma, and YAP activation or FGFR2-alteration are potential biomarkers for response." @default.
• W4205908298 created "2022-01-25" @default.
• W4205908298 creator A5002865415 @default.
• W4205908298 creator A5004470985 @default.
• W4205908298 creator A5006827585 @default.
• W4205908298 creator A5007445103 @default.
• W4205908298 creator A5018257387 @default.
• W4205908298 creator A5018876487 @default.
• W4205908298 creator A5018892762 @default.
• W4205908298 creator A5029404091 @default.
• W4205908298 creator A5041728158 @default.
• W4205908298 creator A5045960752 @default.
• W4205908298 creator A5046143607 @default.
• W4205908298 creator A5048034188 @default.
• W4205908298 creator A5051577648 @default.
• W4205908298 creator A5061507227 @default.
• W4205908298 creator A5064918059 @default.
• W4205908298 creator A5078201989 @default.
• W4205908298 creator A5078788354 @default.
• W4205908298 creator A5091765092 @default.
• W4205908298 date "2022-02-01" @default.
• W4205908298 modified "2023-10-16" @default.
• W4205908298 title "Preclinical evaluation of LCK as a novel therapeutic target in YAP-activated and FGFR2-altered cholangiocarcinoma." @default.
• W4205908298 doi "https://doi.org/10.1200/jco.2022.40.4_suppl.463" @default.
• W4205908298 hasPublicationYear "2022" @default.
• W4205908298 type Work @default.
• W4205908298 citedByCount "0" @default.
• W4205908298 crossrefType "journal-article" @default.
• W4205908298 hasAuthorship W4205908298A5002865415 @default.
• W4205908298 hasAuthorship W4205908298A5004470985 @default.
• W4205908298 hasAuthorship W4205908298A5006827585 @default.
• W4205908298 hasAuthorship W4205908298A5007445103 @default.
• W4205908298 hasAuthorship W4205908298A5018257387 @default.
• W4205908298 hasAuthorship W4205908298A5018876487 @default.
• W4205908298 hasAuthorship W4205908298A5018892762 @default.
• W4205908298 hasAuthorship W4205908298A5029404091 @default.
• W4205908298 hasAuthorship W4205908298A5041728158 @default.
• W4205908298 hasAuthorship W4205908298A5045960752 @default.
• W4205908298 hasAuthorship W4205908298A5046143607 @default.
• W4205908298 hasAuthorship W4205908298A5048034188 @default.
• W4205908298 hasAuthorship W4205908298A5051577648 @default.
• W4205908298 hasAuthorship W4205908298A5061507227 @default.
• W4205908298 hasAuthorship W4205908298A5064918059 @default.
• W4205908298 hasAuthorship W4205908298A5078201989 @default.
• W4205908298 hasAuthorship W4205908298A5078788354 @default.
• W4205908298 hasAuthorship W4205908298A5091765092 @default.
• W4205908298 hasConcept C11960822 @default.
• W4205908298 hasConcept C121608353 @default.
• W4205908298 hasConcept C126322002 @default.
• W4205908298 hasConcept C170493617 @default.
• W4205908298 hasConcept C172512520 @default.
• W4205908298 hasConcept C184235292 @default.
• W4205908298 hasConcept C203014093 @default.
• W4205908298 hasConcept C2778820342 @default.
• W4205908298 hasConcept C2781018059 @default.
• W4205908298 hasConcept C29537977 @default.
• W4205908298 hasConcept C42362537 @default.
• W4205908298 hasConcept C502942594 @default.
• W4205908298 hasConcept C51785407 @default.
• W4205908298 hasConcept C71924100 @default.
• W4205908298 hasConcept C86803240 @default.
• W4205908298 hasConcept C95444343 @default.
• W4205908298 hasConceptScore W4205908298C11960822 @default.
• W4205908298 hasConceptScore W4205908298C121608353 @default.
• W4205908298 hasConceptScore W4205908298C126322002 @default.
• W4205908298 hasConceptScore W4205908298C170493617 @default.
• W4205908298 hasConceptScore W4205908298C172512520 @default.
• W4205908298 hasConceptScore W4205908298C184235292 @default.
• W4205908298 hasConceptScore W4205908298C203014093 @default.
• W4205908298 hasConceptScore W4205908298C2778820342 @default.
• W4205908298 hasConceptScore W4205908298C2781018059 @default.
• W4205908298 hasConceptScore W4205908298C29537977 @default.
• W4205908298 hasConceptScore W4205908298C42362537 @default.
• W4205908298 hasConceptScore W4205908298C502942594 @default.
• W4205908298 hasConceptScore W4205908298C51785407 @default.
• W4205908298 hasConceptScore W4205908298C71924100 @default.
• W4205908298 hasConceptScore W4205908298C86803240 @default.
• W4205908298 hasConceptScore W4205908298C95444343 @default.
• W4205908298 hasFunder F4320332161 @default.
• W4205908298 hasIssue "4_suppl" @default.
• W4205908298 hasLocation W42059082981 @default.
• W4205908298 hasOpenAccess W4205908298 @default.
• W4205908298 hasPrimaryLocation W42059082981 @default.
• W4205908298 hasRelatedWork W2042520059 @default.
• W4205908298 hasRelatedWork W2092128105 @default.
• W4205908298 hasRelatedWork W2124138972 @default.
• W4205908298 hasRelatedWork W2294506205 @default.
• W4205908298 hasRelatedWork W2463369257 @default.
• W4205908298 hasRelatedWork W2467622083 @default.
• W4205908298 hasRelatedWork W2766254106 @default.
• W4205908298 hasRelatedWork W2792929645 @default.
• W4205908298 hasRelatedWork W2809667083 @default.
• W4205908298 hasRelatedWork W4205908298 @default.
• W4205908298 hasVolume "40" @default.
• W4205908298 isParatext "false" @default.
• W4205908298 isRetracted "false" @default.
• W4205908298 workType "article" @default.