Matches in SemOpenAlex for { <https://semopenalex.org/work/W4309108430> ?p ?o ?g. }
Showing items 1 to 80 of
80
with 100 items per page.
- W4309108430 endingPage "B007" @default.
- W4309108430 startingPage "B007" @default.
- W4309108430 abstract "Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression was associated with increased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and increased autophagic flux. We speculated that the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine (CQ) synergistically enhanced ERK inhibitor-mediated anti-proliferative activity. Our findings, together with similar observations by others, provided the rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with hydroxychloroquine (HCQ) in PDAC. Our ongoing studies are centered on developing additional combinations for targeting autophagy. First, we performed a CRISPR/Cas-9 mediated genetic loss-of-function screen in the presence of CQ to determine additional sensitizers as well as mediators of resistance to autophagy inhibition. Top sensitizers included multiple facilitators of the DNA damage response, mTOR pathway components, and genes involved in the upstream regulation of the autophagy pathway. Second, we determined that autophagic signaling is temporally regulated following RAS pathway inhibition and hypothesize that further dissection of this regulation will improve current anti-nutrient scavenging treatment strategies. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment. Citation Format: Jonathan M. DeLiberty, Ryan Robb, Claire E. Gates, Noah L. Pieper, Runying Yang, Clint A. Stalnecker, Kirsten L. Bryant. Enhancing autophagy inhibition as a therapeutic strategy for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B007." @default.
- W4309108430 created "2022-11-22" @default.
- W4309108430 creator A5005237041 @default.
- W4309108430 creator A5008649836 @default.
- W4309108430 creator A5023816378 @default.
- W4309108430 creator A5044479770 @default.
- W4309108430 creator A5055533877 @default.
- W4309108430 creator A5077659587 @default.
- W4309108430 creator A5087221132 @default.
- W4309108430 date "2022-11-15" @default.
- W4309108430 modified "2023-09-25" @default.
- W4309108430 title "Abstract B007: Enhancing autophagy inhibition as a therapeutic strategy for pancreatic cancer" @default.
- W4309108430 doi "https://doi.org/10.1158/1538-7445.panca22-b007" @default.
- W4309108430 hasPublicationYear "2022" @default.
- W4309108430 type Work @default.
- W4309108430 citedByCount "0" @default.
- W4309108430 crossrefType "journal-article" @default.
- W4309108430 hasAuthorship W4309108430A5005237041 @default.
- W4309108430 hasAuthorship W4309108430A5008649836 @default.
- W4309108430 hasAuthorship W4309108430A5023816378 @default.
- W4309108430 hasAuthorship W4309108430A5044479770 @default.
- W4309108430 hasAuthorship W4309108430A5055533877 @default.
- W4309108430 hasAuthorship W4309108430A5077659587 @default.
- W4309108430 hasAuthorship W4309108430A5087221132 @default.
- W4309108430 hasConcept C104317684 @default.
- W4309108430 hasConcept C119056186 @default.
- W4309108430 hasConcept C121608353 @default.
- W4309108430 hasConcept C126322002 @default.
- W4309108430 hasConcept C190283241 @default.
- W4309108430 hasConcept C203522944 @default.
- W4309108430 hasConcept C2780210213 @default.
- W4309108430 hasConcept C2781187634 @default.
- W4309108430 hasConcept C502942594 @default.
- W4309108430 hasConcept C526805850 @default.
- W4309108430 hasConcept C54355233 @default.
- W4309108430 hasConcept C57074206 @default.
- W4309108430 hasConcept C62478195 @default.
- W4309108430 hasConcept C71924100 @default.
- W4309108430 hasConcept C86554907 @default.
- W4309108430 hasConcept C86803240 @default.
- W4309108430 hasConcept C95444343 @default.
- W4309108430 hasConcept C98274493 @default.
- W4309108430 hasConceptScore W4309108430C104317684 @default.
- W4309108430 hasConceptScore W4309108430C119056186 @default.
- W4309108430 hasConceptScore W4309108430C121608353 @default.
- W4309108430 hasConceptScore W4309108430C126322002 @default.
- W4309108430 hasConceptScore W4309108430C190283241 @default.
- W4309108430 hasConceptScore W4309108430C203522944 @default.
- W4309108430 hasConceptScore W4309108430C2780210213 @default.
- W4309108430 hasConceptScore W4309108430C2781187634 @default.
- W4309108430 hasConceptScore W4309108430C502942594 @default.
- W4309108430 hasConceptScore W4309108430C526805850 @default.
- W4309108430 hasConceptScore W4309108430C54355233 @default.
- W4309108430 hasConceptScore W4309108430C57074206 @default.
- W4309108430 hasConceptScore W4309108430C62478195 @default.
- W4309108430 hasConceptScore W4309108430C71924100 @default.
- W4309108430 hasConceptScore W4309108430C86554907 @default.
- W4309108430 hasConceptScore W4309108430C86803240 @default.
- W4309108430 hasConceptScore W4309108430C95444343 @default.
- W4309108430 hasConceptScore W4309108430C98274493 @default.
- W4309108430 hasIssue "22_Supplement" @default.
- W4309108430 hasLocation W43091084301 @default.
- W4309108430 hasOpenAccess W4309108430 @default.
- W4309108430 hasPrimaryLocation W43091084301 @default.
- W4309108430 hasRelatedWork W1999741914 @default.
- W4309108430 hasRelatedWork W2002636911 @default.
- W4309108430 hasRelatedWork W2112087504 @default.
- W4309108430 hasRelatedWork W2267713729 @default.
- W4309108430 hasRelatedWork W2332361683 @default.
- W4309108430 hasRelatedWork W2566402427 @default.
- W4309108430 hasRelatedWork W2620319885 @default.
- W4309108430 hasRelatedWork W2920097475 @default.
- W4309108430 hasRelatedWork W3128531677 @default.
- W4309108430 hasRelatedWork W4221043542 @default.
- W4309108430 hasVolume "82" @default.
- W4309108430 isParatext "false" @default.
- W4309108430 isRetracted "false" @default.
- W4309108430 workType "article" @default.