FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2810709218> ?p ?o ?g. }

• W2810709218 abstract "Background: BRAF V600E mutations occur in ~10% of colorectal cancer (CRC), are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. Using gene expression data from BRAFMT CRC patient samples, we recently identified that dopamine receptor degradation and unfolded protein response are dominant pathways deregulated in the BRAFMT subgroup with the poorest outcome. The aim of this study was to investigate the role of the dopamine receptor 2 (DRD2) pathway as novel target in BRAFMT CRC cells. Methods: Small molecule DRD2 antagonists ONC-201 and ONC-206 (Oncoceutics Inc) and a panel of isogenic paired and non-isogenic BRAFMT and BRAFWT cells were used. MTT, Flow Cytometry, Western blotting and caspase- 8, 3/7 activity assays were used to measure cell survival/death. DR5 cell localization was performed using flow cytometry. A compound library including small molecules approved by the FDA was used. Results: BRAFMT CRC cells were highly sensitive to the DRD2 antagonists ONC-201 and ONC-206 with IC 50 values between 1.9-4.5μM and 0.16 and 0.24μM respectively. Treatment with ONC-201 and ONC-206 resulted in marked increases in expression levels of the endoplasmic reticulum stress proteins ATF4, CHOP and the active (spliced) form of XBP1 (sXBP1) (indicators of activation of the PERK and IRE1α UPR branches), and this was associated with apoptosis induction as indicated by PARP cleavage, caspase-9 cleavage and increased caspase-3/7 activity in the BRAFMT VACO432 cell line but not in the WT VT1 clone. Importantly, no significant effect on proliferation or apoptosis was obtained in the normal colon CCD-18 fibroblast cell line following treatment with ONC-201 or ONC-206. Using a small molecule compound library, we found that the taxanes paclitaxel and docetaxel resulted in strong synergy and apoptosis when combined with ONC-201 or ONC-206, in particular in BRAFMT CRC cells. Mechanistically, we found that the apoptosis induced by combined ONC-201/paclitaxel treatment was dependent on caspase-8 activation and on up-regulation of the death receptor 5 (DR5). Conclusions: Taken together, we have identified a role for DRD2 signalling in the survival of BRAFMT CRC cells. Our data support the development of DRD2 antagonists, in particular in combination with taxanes, for the treatment of BRAFMT CRC tumours. Citation Format: Arman Javadi, Nicholas Forsythe, Alaa Refaat, Jessica-Ann Weir, Hajrah Khawaja, David Waugh, Rohinton Tarapore, Joshua E. Allen, Patrick Johnston, Sandra Van Schaeybroeck. Targeting the dopamine receptor 2 in BRAF mutant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3448." @default.
• W2810709218 created "2018-07-10" @default.
• W2810709218 creator A5008547275 @default.
• W2810709218 creator A5016947205 @default.
• W2810709218 creator A5017072034 @default.
• W2810709218 creator A5017147519 @default.
• W2810709218 creator A5022800910 @default.
• W2810709218 creator A5023638547 @default.
• W2810709218 creator A5026662718 @default.
• W2810709218 creator A5045679809 @default.
• W2810709218 creator A5056678241 @default.
• W2810709218 creator A5069921022 @default.
• W2810709218 date "2018-07-01" @default.
• W2810709218 modified "2023-10-14" @default.
• W2810709218 title "Abstract 3448: Targeting the dopamine receptor 2 inBRAFmutant colorectal cancer" @default.
• W2810709218 doi "https://doi.org/10.1158/1538-7445.am2018-3448" @default.
• W2810709218 hasPublicationYear "2018" @default.
• W2810709218 type Work @default.
• W2810709218 sameAs 2810709218 @default.
• W2810709218 citedByCount "0" @default.
• W2810709218 crossrefType "proceedings-article" @default.
• W2810709218 hasAuthorship W2810709218A5008547275 @default.
• W2810709218 hasAuthorship W2810709218A5016947205 @default.
• W2810709218 hasAuthorship W2810709218A5017072034 @default.
• W2810709218 hasAuthorship W2810709218A5017147519 @default.
• W2810709218 hasAuthorship W2810709218A5022800910 @default.
• W2810709218 hasAuthorship W2810709218A5023638547 @default.
• W2810709218 hasAuthorship W2810709218A5026662718 @default.
• W2810709218 hasAuthorship W2810709218A5045679809 @default.
• W2810709218 hasAuthorship W2810709218A5056678241 @default.
• W2810709218 hasAuthorship W2810709218A5069921022 @default.
• W2810709218 hasConcept C104317684 @default.
• W2810709218 hasConcept C120069818 @default.
• W2810709218 hasConcept C121608353 @default.
• W2810709218 hasConcept C126322002 @default.
• W2810709218 hasConcept C139447449 @default.
• W2810709218 hasConcept C153911025 @default.
• W2810709218 hasConcept C170493617 @default.
• W2810709218 hasConcept C185592680 @default.
• W2810709218 hasConcept C190283241 @default.
• W2810709218 hasConcept C199596767 @default.
• W2810709218 hasConcept C2779725641 @default.
• W2810709218 hasConcept C2781331208 @default.
• W2810709218 hasConcept C502942594 @default.
• W2810709218 hasConcept C526805850 @default.
• W2810709218 hasConcept C54355233 @default.
• W2810709218 hasConcept C54458228 @default.
• W2810709218 hasConcept C553184892 @default.
• W2810709218 hasConcept C67705224 @default.
• W2810709218 hasConcept C71924100 @default.
• W2810709218 hasConcept C86803240 @default.
• W2810709218 hasConceptScore W2810709218C104317684 @default.
• W2810709218 hasConceptScore W2810709218C120069818 @default.
• W2810709218 hasConceptScore W2810709218C121608353 @default.
• W2810709218 hasConceptScore W2810709218C126322002 @default.
• W2810709218 hasConceptScore W2810709218C139447449 @default.
• W2810709218 hasConceptScore W2810709218C153911025 @default.
• W2810709218 hasConceptScore W2810709218C170493617 @default.
• W2810709218 hasConceptScore W2810709218C185592680 @default.
• W2810709218 hasConceptScore W2810709218C190283241 @default.
• W2810709218 hasConceptScore W2810709218C199596767 @default.
• W2810709218 hasConceptScore W2810709218C2779725641 @default.
• W2810709218 hasConceptScore W2810709218C2781331208 @default.
• W2810709218 hasConceptScore W2810709218C502942594 @default.
• W2810709218 hasConceptScore W2810709218C526805850 @default.
• W2810709218 hasConceptScore W2810709218C54355233 @default.
• W2810709218 hasConceptScore W2810709218C54458228 @default.
• W2810709218 hasConceptScore W2810709218C553184892 @default.
• W2810709218 hasConceptScore W2810709218C67705224 @default.
• W2810709218 hasConceptScore W2810709218C71924100 @default.
• W2810709218 hasConceptScore W2810709218C86803240 @default.
• W2810709218 hasLocation W28107092181 @default.
• W2810709218 hasOpenAccess W2810709218 @default.
• W2810709218 hasPrimaryLocation W28107092181 @default.
• W2810709218 hasRelatedWork W1980351711 @default.
• W2810709218 hasRelatedWork W1987233377 @default.
• W2810709218 hasRelatedWork W2072226297 @default.
• W2810709218 hasRelatedWork W2340799657 @default.
• W2810709218 hasRelatedWork W2433986224 @default.
• W2810709218 hasRelatedWork W2539854696 @default.
• W2810709218 hasRelatedWork W2768378107 @default.
• W2810709218 hasRelatedWork W2810709218 @default.
• W2810709218 hasRelatedWork W4242577670 @default.
• W2810709218 hasRelatedWork W787120501 @default.
• W2810709218 isParatext "false" @default.
• W2810709218 isRetracted "false" @default.
• W2810709218 magId "2810709218" @default.
• W2810709218 workType "article" @default.