FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2401921569> ?p ?o ?g. }

• W2401921569 abstract "Activating mutations in the anaplastic lymphoma receptor tyrosine kinase (ALK) represent important therapeutic targets in neuroblastoma (NB). One of the more common mutations, ALKF1174L, is sensitive to the FDA-approved ALK inhibitor, crizotinib, only at high doses and mediates acquired resistance to crizotinib in ALK-rearranged cancers. To identify compounds that would enhance the cytotoxic effect of crizotinib, we conducted a high throughput small molecule screen for compounds that synergize with crizotinib in NB cells expressing the ALKF1174L mutation. We identified two pan-selective cyclin dependent kinase (CDK) inhibitors, AT7519 and SNS-032, which have overlapping efficacy against the cell cycle-regulating CDK2 and transcriptional elongation-regulating CDK9. Both inhibitors demonstrated synergistic activity with crizotinib, leading to downregulation of pALK and downstream signaling and significantly increased apoptosis over that of either single agent alone. This effect was observed in NB cells expressing not only ALKF1174L, but also in the other commonly observed ALKR1275Q mutation. Synergy was also noted with ceritinib (LDK378), a structurally unrelated ALK inhibitor, in combination with both AT7519 and SNS-032. The combination of crizotinib and SNS-032 led to the inhibition of CDK9-mediated transcriptional elongation as indicated by downregulation of RNA polymerase II phosphorylation at serine 2. Additionally, the combination also induced proteolytic cleavage of elongation-regulating BRD4, suggesting alternative mechanisms contributing to transcriptional inhibition in addition to direct inhibition of CDK9 activity These findings were comparable with results obtained using compounds that were highly selective for CDK7, which has roles in transcriptional initiation as well as in CDK9 activation. Finally, in murine xenogaft models of ALK-mutated NB, the combination led to inhibition of tumor growth and prolongation of survival compared to single agents alone. Together, these data support further pre-clinical and clinical efforts to explore the therapeutic potential of combining ALK inhibitors with transcriptional CDK inhibitors in ALK-mutated NB. Citation Format: Nathan F. Moore, Edmond Chipumuro, Clark M. Hatheway, Tinghu Zhang, Nathanael S. Gray, Rani E. George. Combined inhibition of ALK and CDKs involved in transcriptional regulation is synergistic in ALK-mutated neuroblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B74." @default.
• W2401921569 created "2016-06-24" @default.
• W2401921569 creator A5000604617 @default.
• W2401921569 creator A5002000126 @default.
• W2401921569 creator A5014982944 @default.
• W2401921569 creator A5022352605 @default.
• W2401921569 creator A5068507476 @default.
• W2401921569 creator A5076861872 @default.
• W2401921569 date "2015-12-01" @default.
• W2401921569 modified "2023-09-27" @default.
• W2401921569 title "Abstract B74: Combined inhibition of ALK and CDKs involved in transcriptional regulation is synergistic in ALK-mutated neuroblastoma" @default.
• W2401921569 doi "https://doi.org/10.1158/1535-7163.targ-15-b74" @default.
• W2401921569 hasPublicationYear "2015" @default.
• W2401921569 type Work @default.
• W2401921569 sameAs 2401921569 @default.
• W2401921569 citedByCount "0" @default.
• W2401921569 crossrefType "proceedings-article" @default.
• W2401921569 hasAuthorship W2401921569A5000604617 @default.
• W2401921569 hasAuthorship W2401921569A5002000126 @default.
• W2401921569 hasAuthorship W2401921569A5014982944 @default.
• W2401921569 hasAuthorship W2401921569A5022352605 @default.
• W2401921569 hasAuthorship W2401921569A5068507476 @default.
• W2401921569 hasAuthorship W2401921569A5076861872 @default.
• W2401921569 hasConcept C104317684 @default.
• W2401921569 hasConcept C117643217 @default.
• W2401921569 hasConcept C124320809 @default.
• W2401921569 hasConcept C127561419 @default.
• W2401921569 hasConcept C141071460 @default.
• W2401921569 hasConcept C153911025 @default.
• W2401921569 hasConcept C184235292 @default.
• W2401921569 hasConcept C185592680 @default.
• W2401921569 hasConcept C190283241 @default.
• W2401921569 hasConcept C2776232967 @default.
• W2401921569 hasConcept C2776715637 @default.
• W2401921569 hasConcept C2778298596 @default.
• W2401921569 hasConcept C2778347629 @default.
• W2401921569 hasConcept C2779422266 @default.
• W2401921569 hasConcept C2779634585 @default.
• W2401921569 hasConcept C29537977 @default.
• W2401921569 hasConcept C502942594 @default.
• W2401921569 hasConcept C54355233 @default.
• W2401921569 hasConcept C55493867 @default.
• W2401921569 hasConcept C71924100 @default.
• W2401921569 hasConcept C81885089 @default.
• W2401921569 hasConcept C86803240 @default.
• W2401921569 hasConcept C95444343 @default.
• W2401921569 hasConceptScore W2401921569C104317684 @default.
• W2401921569 hasConceptScore W2401921569C117643217 @default.
• W2401921569 hasConceptScore W2401921569C124320809 @default.
• W2401921569 hasConceptScore W2401921569C127561419 @default.
• W2401921569 hasConceptScore W2401921569C141071460 @default.
• W2401921569 hasConceptScore W2401921569C153911025 @default.
• W2401921569 hasConceptScore W2401921569C184235292 @default.
• W2401921569 hasConceptScore W2401921569C185592680 @default.
• W2401921569 hasConceptScore W2401921569C190283241 @default.
• W2401921569 hasConceptScore W2401921569C2776232967 @default.
• W2401921569 hasConceptScore W2401921569C2776715637 @default.
• W2401921569 hasConceptScore W2401921569C2778298596 @default.
• W2401921569 hasConceptScore W2401921569C2778347629 @default.
• W2401921569 hasConceptScore W2401921569C2779422266 @default.
• W2401921569 hasConceptScore W2401921569C2779634585 @default.
• W2401921569 hasConceptScore W2401921569C29537977 @default.
• W2401921569 hasConceptScore W2401921569C502942594 @default.
• W2401921569 hasConceptScore W2401921569C54355233 @default.
• W2401921569 hasConceptScore W2401921569C55493867 @default.
• W2401921569 hasConceptScore W2401921569C71924100 @default.
• W2401921569 hasConceptScore W2401921569C81885089 @default.
• W2401921569 hasConceptScore W2401921569C86803240 @default.
• W2401921569 hasConceptScore W2401921569C95444343 @default.
• W2401921569 hasLocation W24019215691 @default.
• W2401921569 hasOpenAccess W2401921569 @default.
• W2401921569 hasPrimaryLocation W24019215691 @default.
• W2401921569 hasRelatedWork W10107911 @default.
• W2401921569 hasRelatedWork W13475209 @default.
• W2401921569 hasRelatedWork W13627206 @default.
• W2401921569 hasRelatedWork W156741 @default.
• W2401921569 hasRelatedWork W20339032 @default.
• W2401921569 hasRelatedWork W4539665 @default.
• W2401921569 hasRelatedWork W5161616 @default.
• W2401921569 hasRelatedWork W9365724 @default.
• W2401921569 hasRelatedWork W19522458 @default.
• W2401921569 hasRelatedWork W20022638 @default.
• W2401921569 isParatext "false" @default.
• W2401921569 isRetracted "false" @default.
• W2401921569 magId "2401921569" @default.
• W2401921569 workType "article" @default.