biostudies-literatureLi DNIBIB NIH HHSNIAID NIH HHSNCI NIH HHSNIHe174249https://www.ebi.ac.uk/biostudies/studies/S-EPMC11735103biostudies-literatureUnknown135(2)Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robuThe Journal of clinical investigationTargeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.PMC11735103K22CA276357P30 CA047904R01 CA254112P41 EB017183P30CA016087T32 AI007509K22 CA276357P30 CA016087P30 CA015704U01 CA282109K22 CA279077K22 CA258805Nabet BWilliams AMStephens JPloszaj MZhang HGeng KDonald-Paladino MSLevin DSChafitz AWong KKHao YKumar SThakurdin CPowell JMLiu YNacev BAOlson ATChen WGu JKaiza MEWang XChen TKuismi CCKim HMPan YRanieri MLi JLi DChen JZhang ZYLi FBerger AHSherman FGu SSSun XHu BLi YZhang TGray NSBruno TCZhang XHan HMeynardie MfalseTargeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robu2024-01-01T00:00:00Z2024 Dec2026-06-01T13:02:46.159Z2025-04-06T01:17:00.721ZS-EPMC117351033971882810.1172/JCI174249