美国纽约大学医学院Thales Papagiannakopoulos课题组研究发现，癌症中氧化应激反应的激活产生对外源性非必需氨基酸的药物依赖性。相关论文在线发表在2019年12月5日的《细胞—代谢》上。

他们证明具有高抗氧化能力的癌症表现出对外源非必需氨基酸（NEAAs）的一般依赖性，该NEAA由Nrf2依赖性谷氨酸通过系统xc-（XCT）分泌驱动，这限制了NEAA合成所需的细胞内谷氨酸池。这种依赖性，在临床上可以通过饮食限制或单个NEAA酶消耗来靶向。重要的是，通过抑制谷氨酰胺酶来限制内源性谷氨酸水平可以使肿瘤敏感，而不会改变Keap1 / Nrf2途径对NEAAs饮食的限制。他们的发现确定了一种代谢策略，可以通过限制NEAA的外源来源，通过Nrf2抗氧化剂反应途径的遗传或药理学活化来靶向治疗癌症。

研究人员表示，代谢途径的重新布线是肿瘤发生的标志，因为癌细胞获得了新的营养依赖性以支持致癌性生长。具有KEAP1 / NRF2突变的肺腺癌的主要遗传亚型激活内源性氧化应激反应，需要进行大量的新陈代谢，以增强抗氧化剂的产生。

附：英文原文

Title: Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids

Author: Sarah E. LeBoeuf, Warren L. Wu, Triantafyllia R. Karakousi, Burcu Karadal, S. RaElle Jackson, Shawn M. Davidson, Kwok-Kin Wong, Sergei B. Koralov, Volkan I. Sayin, Thales Papagiannakopoulos

Issue&Volume: December 05, 2019

Abstract: Rewiring of metabolic pathways is a hallmark of tumorigenesis as cancer cells acquirenovel nutrient dependencies to support oncogenic growth. A major genetic subtype oflung adenocarcinoma with KEAP1/NRF2 mutations, which activates the endogenous oxidative stress response, undergoes significantmetabolic rewiring to support enhanced antioxidant production. We demonstrate thatcancers with high antioxidant capacity exhibit a general dependency on exogenous non-essentialamino acids (NEAAs) that is driven by the Nrf2-dependent secretion of glutamate throughsystem xc (XCT), which limits intracellular glutamate pools that are required for NEAA synthesis.This dependency can be therapeutically targeted by dietary restriction or enzymaticdepletion of individual NEAAs. Importantly, limiting endogenous glutamate levels byglutaminase inhibition can sensitize tumors without alterations in the Keap1/Nrf2pathway to dietary restriction of NEAAs. Our findings identify a metabolic strategyto therapeutically target cancers with genetic or pharmacologic activation of theNrf2 antioxidant response pathway by restricting exogenous sources of NEAAs.

DOI: 10.1016/j.cmet.2019.11.012

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30619-9