FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4234625556> ?p ?o ?g. }

• W4234625556 endingPage "3008" @default.
• W4234625556 startingPage "3008" @default.
• W4234625556 abstract "Abstract Multiple myeloma (MM) remains an all but incurable malignancy due to minimal residual disease (MRD). MRD is influenced by the survival promoting aspects of the tumor microenvironment (TME) and putative MM cancer stem cells. Therefore, identification of survival determinants specific to the TME and putative MM stem cells is critical for the design of therapy and elimination of MRD. Within the context of the TME, we have shown that collaborative signaling between β1 integrin-mediated adhesion to fibronectin (FN) and Interleukin-6 (IL-6) confers a more malignant phenotype via amplification of STAT3 activation. Further characterization of the events modulated under these culture conditions with quantitative phospho-tyrosine profiling identified 193 differentially phosphorylated peptides after adhesion to FN, treatment with IL-6, and the combination. Phosphopeptides represented proteins involved in signal transduction, cytoskeleton assembly/adhesion, transcription, RNA processing, metabolism, and the cell cycle. Seventy-seven phosphorylations were up-regulated upon adhesion, including PYK2/FAK2, paxillin, CASL, and p130CAS consistent with focal adhesion (FA) formation. Western blot analysis demonstrated PYK2 autophosphorylation of Y402 following myeloma cell adhesion to FN or bone marrow stromal cells (BMSC), correlating with the amplification of IL-6-induced STAT3 and JAK1. We hypothesized that the collaborative signaling between β1 integrin and the IL-6 signal transducer, gp130, was mediated by FA formation and PYK2. Assessing downstream gene expression, we also demonstrated that adhesion to FN alone or co-stimulation with FN and IL-6 upregulated mRNA and protein expression of the MM survival-associated gene, deptor, and this enhanced expression was abrogated by RNAi knockdown of STAT3 or PYK2. Both pharmacological and molecular targeting of PYK2 attenuated the amplification of STAT3 phosphorylation in adhered cells. Importantly, MM cells co-cultured with patient BMSCs showed similar gp130 and β1 integrin-specific enhancement of PYK2, JAK1, STAT3 signaling when adhered to patient BMSCs, demonstrating that PYK2 modulates co-stimulation specific STAT3 signaling in more complex, clinically relevant models of the microenvironment. Interestingly, targeting PYK2 with antisense oligonucleotides (ISIS Pharmaceuticals) or with the dual PYK2/FAK (Focal adhesion kinase) tyrosine kinase inhibitors VS-4718, VS-6062, and VS-6063 (Verastem, Inc.) induced preferential MM cell killing in the context of adhesion to patient BMSCs, but not in monoculture or under transwell co-culture conditions. We confirmed that this cell death correlated with inhibition of BMSC-induced PYK2 and STAT3 phosphorylation. Further analysis similarly demonstrated a preferential reduction in colony formation in BMSC-adherent MM cell lines and patient specimens treated with VS-6063 relative to MM cells in the absence of BMSCs. Co-culture with BMSCs also increased the percentage of ALDH+ MM cancer stem cells relative to monoculture. Therefore, we examined the effects of targeting PYK2 with VS-6063 in ALDH+ MM cancer stem cells. VS-6063 decreased the percentage of the ALDH+ cells associated with BMSC to greater degree than MM cells without BMSC. These data identify a novel PYK2-mediated survival pathway activated within the context of multiple microenvironmental cues, suggesting that PYK2 is a TME-specific therapeutic target. Further, putative MM cancer stem cells are sensitive to PYK2 inhibition by the FAK/PYK2 inhibitor VS-6063. Lastly, we examined the role of PYK2 in an in vivo model of the TME. Oral administration of the VS-4718 PYK2/FAK TKI twice daily significantly reduced murine myeloma disease burden as quantified by IgG2b levels and luciferase activity (p= 0.03 and 0.02). Treatment with VS-4718 also afforded a statistically significant overall survival advantage to treated mice relative to vehicle control (p=0.018). As such, these data indicate that PYK2 may be a critical target for the eradication of MRD by targeting both MM cells in the context of TME and MM cancer stem cells. These results suggest that MM represents a compelling clinical development path for FAK/PYK2 inhibitors, such as VS-4718 and VS-6063, in clinical trials focusing on eradication of MRD. Disclosures Weaver: Verastem: Employment, Equity Ownership. Pachter:Verastem: Employment, Equity Ownership." @default.
• W4234625556 created "2022-05-12" @default.
• W4234625556 creator A5001167914 @default.
• W4234625556 creator A5002876951 @default.
• W4234625556 creator A5014350127 @default.
• W4234625556 creator A5017012258 @default.
• W4234625556 creator A5017064479 @default.
• W4234625556 creator A5027419360 @default.
• W4234625556 creator A5035926085 @default.
• W4234625556 creator A5053572690 @default.
• W4234625556 creator A5054463097 @default.
• W4234625556 creator A5071565523 @default.
• W4234625556 creator A5073334746 @default.
• W4234625556 creator A5073675187 @default.
• W4234625556 creator A5074838425 @default.
• W4234625556 creator A5076672524 @default.
• W4234625556 creator A5083440937 @default.
• W4234625556 date "2015-12-03" @default.
• W4234625556 modified "2023-10-18" @default.
• W4234625556 title "Targeting PYK2 Mediates Microenvironment-Specific Myeloma Cell Death" @default.
• W4234625556 doi "https://doi.org/10.1182/blood.v126.23.3008.3008" @default.
• W4234625556 hasPublicationYear "2015" @default.
• W4234625556 type Work @default.
• W4234625556 citedByCount "0" @default.
• W4234625556 crossrefType "journal-article" @default.
• W4234625556 hasAuthorship W4234625556A5001167914 @default.
• W4234625556 hasAuthorship W4234625556A5002876951 @default.
• W4234625556 hasAuthorship W4234625556A5014350127 @default.
• W4234625556 hasAuthorship W4234625556A5017012258 @default.
• W4234625556 hasAuthorship W4234625556A5017064479 @default.
• W4234625556 hasAuthorship W4234625556A5027419360 @default.
• W4234625556 hasAuthorship W4234625556A5035926085 @default.
• W4234625556 hasAuthorship W4234625556A5053572690 @default.
• W4234625556 hasAuthorship W4234625556A5054463097 @default.
• W4234625556 hasAuthorship W4234625556A5071565523 @default.
• W4234625556 hasAuthorship W4234625556A5073334746 @default.
• W4234625556 hasAuthorship W4234625556A5073675187 @default.
• W4234625556 hasAuthorship W4234625556A5074838425 @default.
• W4234625556 hasAuthorship W4234625556A5076672524 @default.
• W4234625556 hasAuthorship W4234625556A5083440937 @default.
• W4234625556 hasConcept C1491633281 @default.
• W4234625556 hasConcept C151166631 @default.
• W4234625556 hasConcept C16930146 @default.
• W4234625556 hasConcept C195687474 @default.
• W4234625556 hasConcept C2776107976 @default.
• W4234625556 hasConcept C3020616263 @default.
• W4234625556 hasConcept C502942594 @default.
• W4234625556 hasConcept C54355233 @default.
• W4234625556 hasConcept C62478195 @default.
• W4234625556 hasConcept C85789140 @default.
• W4234625556 hasConcept C86803240 @default.
• W4234625556 hasConcept C95444343 @default.
• W4234625556 hasConceptScore W4234625556C1491633281 @default.
• W4234625556 hasConceptScore W4234625556C151166631 @default.
• W4234625556 hasConceptScore W4234625556C16930146 @default.
• W4234625556 hasConceptScore W4234625556C195687474 @default.
• W4234625556 hasConceptScore W4234625556C2776107976 @default.
• W4234625556 hasConceptScore W4234625556C3020616263 @default.
• W4234625556 hasConceptScore W4234625556C502942594 @default.
• W4234625556 hasConceptScore W4234625556C54355233 @default.
• W4234625556 hasConceptScore W4234625556C62478195 @default.
• W4234625556 hasConceptScore W4234625556C85789140 @default.
• W4234625556 hasConceptScore W4234625556C86803240 @default.
• W4234625556 hasConceptScore W4234625556C95444343 @default.
• W4234625556 hasIssue "23" @default.
• W4234625556 hasLocation W42346255561 @default.
• W4234625556 hasOpenAccess W4234625556 @default.
• W4234625556 hasPrimaryLocation W42346255561 @default.
• W4234625556 hasRelatedWork W18145972 @default.
• W4234625556 hasRelatedWork W279647 @default.
• W4234625556 hasRelatedWork W2818275 @default.
• W4234625556 hasRelatedWork W33570450 @default.
• W4234625556 hasRelatedWork W5322158 @default.
• W4234625556 hasRelatedWork W53607375 @default.
• W4234625556 hasRelatedWork W5422456 @default.
• W4234625556 hasRelatedWork W65357492 @default.
• W4234625556 hasRelatedWork W68397822 @default.
• W4234625556 hasRelatedWork W7415094 @default.
• W4234625556 hasVolume "126" @default.
• W4234625556 isParatext "false" @default.
• W4234625556 isRetracted "false" @default.
• W4234625556 workType "article" @default.