FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2479261316> ?p ?o ?g. }

• W2479261316 abstract "The objective of this study is to investigate the genomic and transcriptonal changes that are associated with resistance to treatment with the combination of a PI3K-inhibitor (NVP-BKM120) and a PARP-inhibitor (Olaparib). Previous studies have shown that the combination of a PI3K-inhibitor and a PARP-inhibitor synergistically reduced the growth of BRCA-related xenograft tumors derived from patients with TNBC. However, in clinical practice, primary and secondary resistance to this combination is observed. We hypothesize that acquired resistance is the result of a genomic evolution resulting from the selection pressure exerted by the drug treatment. We used a genetically engineered mouse model, K14-Cre BRCA1f/fp53f/f, where primary tumors had been propagated in Cre-negative littermates and treated to point of resistance with NVP-BKM120 or NVP-BKM120 plus Olaparib. For each of the three tumors, we analyzed exome sequencing and RNA-seq using Illumina technology at the stage of sensitivity (C), resistance to PI3K-inhibition (B) and resistance to the combination (BO); i.e. for each individual tumor a parental clone and its drug-resistant subclones, obtained in vivo, were analyzed. We used the Mutect software tool to call somatic mutations, VarScan2 to call somatic copy number variations, Cuffdiff for differential expression analysis, and TophatFusion. Data were integrated to identify genes for functional analyses using MetaCore and MSigDB software tools. We found that tumors resistant to the combination drug treatment in general had fewer gross genomic alterations (CNVs) than parental tumors, indicative of evolution of a less variable subclone. However, these tumors also displayed a higher number of non-synonymous mutations than their parental clone. Pathway analysis showed that somatically mutated genes in PI3K-inhibitor resistant tumors were highly enriched for antigen processing and presentation, while those of tumors resistant to the combination treatment were enriched for histone modification pathways. Notably, the tumors resistant to PI3K-inhibitor alone were enriched for Insulin-processing pathways. Genomic losses in PI3K-inhibitor treated tumors enriched for the estrogen receptor pathway (ESR) in breast cancer and DNA damage pathways. In conclusion, our experimental design of analyzing isogenic tumors resistant to PI3K- or combined PI3K- and Parp-inhibitors enabled us to identify genomic alterations and pathways that explain the evolution to drug resistance. Citation Format: Sheida Nabavi, Ashish Juvekar, Nicholas Wang, Lewis C. Cantley, Gerburg M. Wulf. Analysis of resistance to the combination of a PI3K- and Parp-inhibitor using a genomic sequencing approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 159." @default.
• W2479261316 created "2016-08-23" @default.
• W2479261316 creator A5010254642 @default.
• W2479261316 creator A5013857834 @default.
• W2479261316 creator A5018472888 @default.
• W2479261316 creator A5057032257 @default.
• W2479261316 creator A5080610604 @default.
• W2479261316 date "2016-07-15" @default.
• W2479261316 modified "2023-09-26" @default.
• W2479261316 title "Abstract 159: Analysis of resistance to the combination of a PI3K- and Parp-inhibitor using a genomic sequencing approach" @default.
• W2479261316 doi "https://doi.org/10.1158/1538-7445.am2016-159" @default.
• W2479261316 hasPublicationYear "2016" @default.
• W2479261316 type Work @default.
• W2479261316 sameAs 2479261316 @default.
• W2479261316 citedByCount "0" @default.
• W2479261316 crossrefType "proceedings-article" @default.
• W2479261316 hasAuthorship W2479261316A5010254642 @default.
• W2479261316 hasAuthorship W2479261316A5013857834 @default.
• W2479261316 hasAuthorship W2479261316A5018472888 @default.
• W2479261316 hasAuthorship W2479261316A5057032257 @default.
• W2479261316 hasAuthorship W2479261316A5080610604 @default.
• W2479261316 hasConcept C104317684 @default.
• W2479261316 hasConcept C114851261 @default.
• W2479261316 hasConcept C134305767 @default.
• W2479261316 hasConcept C16671776 @default.
• W2479261316 hasConcept C182979987 @default.
• W2479261316 hasConcept C190283241 @default.
• W2479261316 hasConcept C2779138821 @default.
• W2479261316 hasConcept C2779962180 @default.
• W2479261316 hasConcept C501734568 @default.
• W2479261316 hasConcept C502942594 @default.
• W2479261316 hasConcept C54355233 @default.
• W2479261316 hasConcept C76818968 @default.
• W2479261316 hasConcept C82381507 @default.
• W2479261316 hasConcept C86554907 @default.
• W2479261316 hasConcept C86803240 @default.
• W2479261316 hasConceptScore W2479261316C104317684 @default.
• W2479261316 hasConceptScore W2479261316C114851261 @default.
• W2479261316 hasConceptScore W2479261316C134305767 @default.
• W2479261316 hasConceptScore W2479261316C16671776 @default.
• W2479261316 hasConceptScore W2479261316C182979987 @default.
• W2479261316 hasConceptScore W2479261316C190283241 @default.
• W2479261316 hasConceptScore W2479261316C2779138821 @default.
• W2479261316 hasConceptScore W2479261316C2779962180 @default.
• W2479261316 hasConceptScore W2479261316C501734568 @default.
• W2479261316 hasConceptScore W2479261316C502942594 @default.
• W2479261316 hasConceptScore W2479261316C54355233 @default.
• W2479261316 hasConceptScore W2479261316C76818968 @default.
• W2479261316 hasConceptScore W2479261316C82381507 @default.
• W2479261316 hasConceptScore W2479261316C86554907 @default.
• W2479261316 hasConceptScore W2479261316C86803240 @default.
• W2479261316 hasLocation W24792613161 @default.
• W2479261316 hasOpenAccess W2479261316 @default.
• W2479261316 hasPrimaryLocation W24792613161 @default.
• W2479261316 hasRelatedWork W1597017743 @default.
• W2479261316 hasRelatedWork W2017153937 @default.
• W2479261316 hasRelatedWork W2040330598 @default.
• W2479261316 hasRelatedWork W2050105520 @default.
• W2479261316 hasRelatedWork W2059328247 @default.
• W2479261316 hasRelatedWork W2117077597 @default.
• W2479261316 hasRelatedWork W2141375939 @default.
• W2479261316 hasRelatedWork W2183855403 @default.
• W2479261316 hasRelatedWork W2185118998 @default.
• W2479261316 hasRelatedWork W2355707553 @default.
• W2479261316 hasRelatedWork W2398119168 @default.
• W2479261316 hasRelatedWork W2592504816 @default.
• W2479261316 hasRelatedWork W2741916920 @default.
• W2479261316 hasRelatedWork W2750605024 @default.
• W2479261316 hasRelatedWork W2890790212 @default.
• W2479261316 hasRelatedWork W2902693794 @default.
• W2479261316 hasRelatedWork W2921626840 @default.
• W2479261316 hasRelatedWork W2985196709 @default.
• W2479261316 hasRelatedWork W3161691011 @default.
• W2479261316 hasRelatedWork W3142775948 @default.
• W2479261316 isParatext "false" @default.
• W2479261316 isRetracted "false" @default.
• W2479261316 magId "2479261316" @default.
• W2479261316 workType "article" @default.