Journal article
KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation
Cell reports (Cambridge), v 44(4), 115444
22 Apr 2025
PMID: 40131933
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Oncogenic KRAS mutations are prevalent in colorectal cancer (CRC) and linked to poor prognosis and therapeutic resistance. Emerging evidence suggests that specific KRAS mutations differentially influence treatment responses. In this study, we generate isogenic Apc-null mouse colon epithelial cells with four common KRAS mutations. Transcriptomic and proteomic analyses reveal significant enrichment of cholesterol and lipid metabolism pathways in KRAS G12V cells, driven by increased SREBP1 expression and mTORC1 activation. Furthermore, KRAS G12V cells exhibit elevated ACSS2 expression and greater dependence on ACSS2 for proliferative advantage compared to other mutants. Inhibition of ACSS2 uniquely sensitizes KRAS G12V cells to MEK inhibition, highlighting a distinct therapeutic vulnerability. Finally, ACSS2 plays a critical role in early KRAS G12V adenoma development, unlike in KRAS G12D adenomas. These findings highlight mutation-specific metabolic reprogramming in KRAS-driven CRC and identify ACSS2 as a potential therapeutic target.
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•KRAS G12V activates distinct signaling pathways in Apc-null mouse colon adenoma cells•Cells expressing KRAS G12V exhibit decreased sensitivity to downstream pathway inhibitors•KRAS G12V cells show enhanced dependance on ACSS2 to generate acetyl-CoA from acetate•Targeting ACSS2 in KRAS G12V cells impacts tumorigenicity and sensitivity to MEK inhibition
Budagyan et al. demonstrate that different KRAS oncogene mutations drive distinct signaling programs in colon adenoma cells. Specifically, KRAS G12V cells exhibit unique metabolic dependency on ACSS2 and acetate metabolism for proliferative advantage. Targeting ACSS2 selectively sensitizes KRAS G12V cells to downstream inhibition, revealing a therapeutic vulnerability.
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Details
- Title
- KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation
- Creators
- Konstantin Budagyan - Drexel UniversityAlexa C. Cannon - Drexel UniversityAdam Chatoff - Temple UniversityDorothy Benton - Drexel UniversityAlison M. Kurimchak - Fox Chase Cancer CenterDaniela Araiza-Olivera - Fox Chase Cancer CenterAnastasiia Gerasimova - Fox Chase Cancer CenterNathaniel W. Snyder - Fox Chase Cancer CenterJames S. Duncan - Fox Chase Cancer CenterCristina Uribe-Alvarez - Fox Chase Cancer CenterJonathan Chernoff (Corresponding Author) - Fox Chase Cancer Center
- Publication Details
- Cell reports (Cambridge), v 44(4), 115444
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; A.J. Drexel Autism Institute
- Web of Science ID
- WOS:001458297200001
- Scopus ID
- 2-s2.0-105000504453
- Other Identifier
- 991022197434104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology