Budagyan Konstantin, Cannon Alexa C, Chatoff Adam, Benton Dorothy, Kurimchak Alison M, Araiza-Olivera Daniela, Gerasimova Anastasiia, Snyder Nathaniel W, Duncan James S, Uribe-Alvarez Cristina, Chernoff Jonathan
Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Cancer & Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Cell Rep. 2025 Apr 22;44(4):115444. doi: 10.1016/j.celrep.2025.115444. Epub 2025 Mar 24.
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.
致癌性KRAS突变在结直肠癌（CRC）中普遍存在，并与预后不良和治疗耐药性相关。新出现的证据表明，特定的KRAS突变对治疗反应有不同的影响。在本研究中，我们生成了具有四种常见KRAS突变的同基因Apc缺失小鼠结肠上皮细胞。转录组学和蛋白质组学分析显示，在KRAS G12V细胞中，胆固醇和脂质代谢途径显著富集，这是由SREBP1表达增加和mTORC1激活驱动的。此外，与其他突变体相比，KRAS G12V细胞表现出ACSS2表达升高，并且对ACSS2的增殖优势依赖性更强。抑制ACSS2能使KRAS G12V细胞对MEK抑制特别敏感，突出了一种独特的治疗脆弱性。最后，与KRAS G12D腺瘤不同，ACSS2在早期KRAS G12V腺瘤发展中起关键作用。这些发现突出了KRAS驱动的CRC中特定突变的代谢重编程，并将ACSS2确定为一个潜在的治疗靶点。
