School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Cancer Res. 2024 Jun 14;84(12):1963-1977. doi: 10.1158/0008-5472.CAN-23-2095.
The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypoacetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC.
ASS1 deficiency is induced by mutant KRAS in NSCLC to facilitate DNA synthesis and creates a dependency on SLC7A1, revealing dietary arginine restriction and SLC7A1 inhibition as potential therapeutic strategies.
癌细胞中的尿素循环经常被重新布线，以满足癌细胞的代谢需求。阐明致癌信号转导介导尿素循环重编程的潜在机制，可以帮助确定可靶向的代谢脆弱性。在这项研究中，我们发现非小细胞肺癌（NSCLC）中的致癌性 KRAS 激活沉默了精氨酸琥珀酸合成酶 1（ASS1）的表达，ASS1 是一种尿素循环酶，可催化精氨酸从天冬氨酸和瓜氨酸生成，从而将天冬氨酸的利用转向嘧啶合成，以满足 DNA 复制的高需求。具体而言，KRAS 信号通过组蛋白去乙酰化酶 3 依赖性方式促进 ASS1 基因启动子区域的低乙酰化状态，进而阻碍 c-MYC 募集进行 ASS1 转录。KRAS 突变 NSCLC 细胞中 ASS1 的抑制会损害精氨酸的生物合成，并使其依赖于精氨酸跨膜转运蛋白 SLC7A1 来摄取细胞外精氨酸。在患者衍生的类器官和异种移植模型中耗尽 SLC7A1 会抑制 KRAS 驱动的 NSCLC 生长。总之，这些发现揭示了致癌性 KRAS 在重新布线尿素循环代谢中的作用，并确定 SLC7A1 介导的精氨酸摄取是治疗 KRAS 突变型 NSCLC 的潜在治疗弱点。
ASS1 缺陷是 NSCLC 中的突变 KRAS 诱导的，以促进 DNA 合成，并产生对 SLC7A1 的依赖性，表明饮食中精氨酸限制和 SLC7A1 抑制可能是潜在的治疗策略。
