FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4367603622> ?p ?o ?g. }

• W4367603622 endingPage "A001" @default.
• W4367603622 startingPage "A001" @default.
• W4367603622 abstract "Abstract Sotorasib demonstrated efficacy in patients with non-small cell lung cancer (NSCLC). However, a substantial proportion of patients do not respond. There is therefore a clear need for a predictive biomarker to guide treatment decisions. Proximity ligation assay (PLA) is an immunofluorescent-based approach for analysis of endogenous protein-protein interactions, in which the signal can be detected only when two target proteins are within 40 nm. This method measures drug-targetable signaling-associated protein complexes in cells and tissues. KRAS activity has recently been shown to be related to the sensitivity to sotorasib. We therefore conducted a preclinical study to evaluate whether RAS activation inferred by PLA might predict response to KRASG12C inhibitors. We first examined panRAS:CRAF PLA reaction for a KRASG12C-mutant H358 NSCLC cell line, by comparing a complete PLA reaction with both panRAS and CRAF antibodies and an incomplete PLA reaction in the absence of either panRAS or CRAF antibodies. We observed high panRAS:CRAF PLA intensity in H358 with both antibodies, which was abrogated in the absence of either panRAS or CRAF antibodies. We next evaluated the specificity of the PLA reaction by RNA interference. Transfection with sipanRAS or siCRAF resulted in a reduction in panRAS:CRAF PLA signal. We then performed panRAS:CRAF PLA with a panel of KRAS G12C-mutant NSCLC cell lines. The intensity of panRAS:CRAF PLA signal varied between these cell lines, with H358 and LU65 having higher and H1792 and LU99 having lower intensity of panRAS:CRAF PLA signal. To further understand the RAS-RAF interaction, we evaluated a CRAF-RAS binding domain pulldown assay for the cell lines. Different levels of CRAF-bound panRAS were observed in the cell lines, with H358 and LU65 having higher and H1792 and LU99 having lower level of CRAF-bound panRAS. The intensity of panRAS:CRAF PLA strongly correlated with CRAF-bound panRAS (r = 0.70, P = 0.037), suggesting that panRAS:CRAF PLA works sufficiently well to detect the RAS-RAF complex. We investigated the antitumor efficacy of AMG510 in vitro and found that a heterogeneous response to AMG510 was observed in the cell lines, with the 50% inhibitory concentration values of AMG510 for H358 and LU65 below 30 nmol/L and those for H1792, and LU99 above 10 μmol/L. The intensity of panRAS:CRAF PLA was strongly associated with the sensitivity of the G12C-mutated cells to AMG510 (r = 0.74, P = 0.01). We next examined sections of FFPE tumors from NSCLC cell line-derived xenograft models. The panRAS:CRAF PLA signal was higher in mice with sotorasib-sensitive H358 than with resistant H1792 (P = 0.02). Our results suggest that RAS:RAF PLA may have values as a predictive marker to identify which patients can obtain the greatest benefit from sotorasib. Citation Format: Ryoji Kato, Hitendra S. Solanki, Denis Imbody, Anurima Majumder, Yaakov Stern, Liznair Bridenstine, Joseph Johnson, Eric B. Haura. RAS:RAF proximity ligation assay may predict response to KRASG12C inhibitors in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A001." @default.
• W4367603622 created "2023-05-02" @default.
• W4367603622 creator A5014162686 @default.
• W4367603622 creator A5025310869 @default.
• W4367603622 creator A5033834811 @default.
• W4367603622 creator A5035455861 @default.
• W4367603622 creator A5058864560 @default.
• W4367603622 creator A5064494204 @default.
• W4367603622 creator A5083986203 @default.
• W4367603622 creator A5084044944 @default.
• W4367603622 date "2023-05-01" @default.
• W4367603622 modified "2023-10-18" @default.
• W4367603622 title "Abstract A001: RAS:RAF proximity ligation assay may predict response to KRASG12C inhibitors in NSCLC" @default.
• W4367603622 doi "https://doi.org/10.1158/1557-3125.ras23-a001" @default.
• W4367603622 hasPublicationYear "2023" @default.
• W4367603622 type Work @default.
• W4367603622 citedByCount "0" @default.
• W4367603622 crossrefType "journal-article" @default.
• W4367603622 hasAuthorship W4367603622A5014162686 @default.
• W4367603622 hasAuthorship W4367603622A5025310869 @default.
• W4367603622 hasAuthorship W4367603622A5033834811 @default.
• W4367603622 hasAuthorship W4367603622A5035455861 @default.
• W4367603622 hasAuthorship W4367603622A5058864560 @default.
• W4367603622 hasAuthorship W4367603622A5064494204 @default.
• W4367603622 hasAuthorship W4367603622A5083986203 @default.
• W4367603622 hasAuthorship W4367603622A5084044944 @default.
• W4367603622 hasConcept C121608353 @default.
• W4367603622 hasConcept C126322002 @default.
• W4367603622 hasConcept C153911025 @default.
• W4367603622 hasConcept C159654299 @default.
• W4367603622 hasConcept C16613235 @default.
• W4367603622 hasConcept C170493617 @default.
• W4367603622 hasConcept C203014093 @default.
• W4367603622 hasConcept C2776243700 @default.
• W4367603622 hasConcept C2781187634 @default.
• W4367603622 hasConcept C2781197716 @default.
• W4367603622 hasConcept C502942594 @default.
• W4367603622 hasConcept C526805850 @default.
• W4367603622 hasConcept C54009773 @default.
• W4367603622 hasConcept C542903549 @default.
• W4367603622 hasConcept C54355233 @default.
• W4367603622 hasConcept C55493867 @default.
• W4367603622 hasConcept C71924100 @default.
• W4367603622 hasConcept C81885089 @default.
• W4367603622 hasConcept C86803240 @default.
• W4367603622 hasConceptScore W4367603622C121608353 @default.
• W4367603622 hasConceptScore W4367603622C126322002 @default.
• W4367603622 hasConceptScore W4367603622C153911025 @default.
• W4367603622 hasConceptScore W4367603622C159654299 @default.
• W4367603622 hasConceptScore W4367603622C16613235 @default.
• W4367603622 hasConceptScore W4367603622C170493617 @default.
• W4367603622 hasConceptScore W4367603622C203014093 @default.
• W4367603622 hasConceptScore W4367603622C2776243700 @default.
• W4367603622 hasConceptScore W4367603622C2781187634 @default.
• W4367603622 hasConceptScore W4367603622C2781197716 @default.
• W4367603622 hasConceptScore W4367603622C502942594 @default.
• W4367603622 hasConceptScore W4367603622C526805850 @default.
• W4367603622 hasConceptScore W4367603622C54009773 @default.
• W4367603622 hasConceptScore W4367603622C542903549 @default.
• W4367603622 hasConceptScore W4367603622C54355233 @default.
• W4367603622 hasConceptScore W4367603622C55493867 @default.
• W4367603622 hasConceptScore W4367603622C71924100 @default.
• W4367603622 hasConceptScore W4367603622C81885089 @default.
• W4367603622 hasConceptScore W4367603622C86803240 @default.
• W4367603622 hasIssue "5_Supplement" @default.
• W4367603622 hasLocation W43676036221 @default.
• W4367603622 hasOpenAccess W4367603622 @default.
• W4367603622 hasPrimaryLocation W43676036221 @default.
• W4367603622 hasRelatedWork W1973692620 @default.
• W4367603622 hasRelatedWork W1992169430 @default.
• W4367603622 hasRelatedWork W2009889818 @default.
• W4367603622 hasRelatedWork W2095050670 @default.
• W4367603622 hasRelatedWork W2102639438 @default.
• W4367603622 hasRelatedWork W2347120132 @default.
• W4367603622 hasRelatedWork W2368460920 @default.
• W4367603622 hasRelatedWork W2379152510 @default.
• W4367603622 hasRelatedWork W2380360044 @default.
• W4367603622 hasRelatedWork W2384261171 @default.
• W4367603622 hasVolume "21" @default.
• W4367603622 isParatext "false" @default.
• W4367603622 isRetracted "false" @default.
• W4367603622 workType "article" @default.