Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Hematology and Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA.
Division of Hematology and Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA.
Cancer Cell. 2018 Jan 8;33(1):91-107.e6. doi: 10.1016/j.ccell.2017.12.003.
KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation. Inhibition of AKT suppressed ASNS expression and, combined with depletion of extracellular asparagine, decreased tumor growth. Therefore, KRAS is important for the cellular response to nutrient stress, and ASNS represents a promising therapeutic target in KRAS mutant NSCLC.
KRAS 是调节非小细胞肺癌（NSCLC）营养压力反应的一个关键因子。在营养物质匮乏时，ATF4 途径的诱导需要 KRAS 下游的 AKT 和 NRF2。肿瘤抑制因子 KEAP1 强烈影响营养压力下该途径激活的结果；KRAS 突变细胞中 KEAP1 的缺失会导致细胞凋亡。通过 ATF4 的调控，KRAS 改变了氨基酸的摄取和天冬酰胺的生物合成。ATF4 的靶标天冬酰胺合成酶（ASNS）有助于抑制细胞凋亡、蛋白质生物合成和 mTORC1 的激活。抑制 AKT 会抑制 ASNS 的表达，与细胞外天冬酰胺的耗竭相结合，会降低肿瘤的生长。因此，KRAS 对细胞对营养压力的反应非常重要，ASNS 是 KRAS 突变 NSCLC 中有前途的治疗靶点。
