Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Mol Cancer Res. 2019 Jun;17(6):1351-1364. doi: 10.1158/1541-7786.MCR-18-1068. Epub 2019 Feb 26.
Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non-small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR. IMPLICATIONS: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFR-driven NSCLC.
致癌基因和肿瘤抑制基因的突变产生了独特的代谢表型,对肿瘤细胞的存活至关重要。EGFR 信号与非小细胞肺癌(NSCLC)中肿瘤代谢的重排有关。我们整合了功能基因组筛选和代谢组学的使用,以确定 EGFR 抑制诱导的代谢脆弱性。这些研究表明,在 EGFR 抑制后,EGFR 驱动的 NSCLC 细胞依赖于尿素循环,特别是尿素循环酶 CPS1。CPS1 的敲低与 EGFR 抑制相结合,进一步降低细胞增殖并阻碍细胞周期进程。代谢组学分析表明,CPS1 的抑制增强了 EGFR 抑制对中央碳代谢、嘧啶生物合成和精氨酸代谢的影响,同时伴随着糖酵解和线粒体呼吸的减少。我们表明,EGFR 抑制和 CPS1 敲低导致精氨酸水平和嘧啶衍生物的降低,并且添加外源性嘧啶部分挽救了细胞生长的损伤。最后,我们表明,在公共可用数据库中,肺癌腺癌中 CPS1 的高表达与患者预后较差相关。这些数据共同揭示了 NSCLC 细胞对尿素循环有更大的依赖性,以维持中央碳代谢、嘧啶生物合成和精氨酸代谢,从而在 EGFR 抑制时满足细胞能量需求。
我们的结果表明,在 EGFR 抑制的情况下,尿素循环可能是一种新的代谢脆弱性,为开发与 EGFR 抑制剂联合使用的合理联合治疗方法提供了机会,用于治疗 EGFR 驱动的 NSCLC。