LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma
LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma
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DOI：
10.1158/0008-5472.can-18-3527
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发表时间：
2019-07-01
期刊：
影响因子：
11.2
通讯作者：
Heymach, John, V
中科院分区：
文献类型：
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作者：
Galan-Cobo, Ana;Sitthideatphaiboon, Piyada;Heymach, John, V
在kras突变型肺腺癌中，LKB1缺失（KL）的肿瘤高度富集同时发生的KEAP1突变，激活KEAP1/NRF2通路（KLK）。在这里，我们研究了这些共同发生的改变的生物学后果，并探讨了它们是否赋予了特定的治疗脆弱性。与KL肿瘤相比，KLK肿瘤中参与谷氨酰胺代谢、三羧酸循环和氧化还原稳态特征的基因表达增加。通过对LKB1、KEAP1和NRF2敲低或过表达的等基因对，我们发现LKB1缺失导致能量和氧化还原应激增加，其特征是细胞内活性氧水平升高，ATP、NADPH/NADP（+）比值和谷胱甘肽水平降低。在lkb1缺陷细胞中，激活KEAP1/NRF2轴可提高细胞存活率，并以谷氨酰胺依赖的方式在维持能量和氧化还原稳态中发挥关键作用。在体外和体内实验中，LKB1和KEAP1/NRF2通路共同驱动代谢重编程，并增强对谷氨酰胺酶抑制剂CB-839的敏感性。总的来说，这些发现阐明了KEAP1/NRF2通路激活在KL肿瘤中提供的适应性优势，并支持了谷氨酰胺酶抑制剂在kras突变肺腺癌亚群中的临床试验。意义：在kras突变型非小细胞肺癌中，LKB1缺失导致能量/氧化还原应激增强，这在一定程度上是通过共同发生KEAP1/ nrf2依赖性代谢适应而耐受的，从而增强了谷氨酰胺依赖性和对谷氨酰胺酶抑制的易损性。
In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated the biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic pairs with knockdown or overexpression of LKB1, KEAP1, and NRF2, we found that LKB1 loss results in increased energetic and redox stress marked by increased levels of intracellular reactive oxygen species and decreased levels of ATP, NADPH/NADP(+) ratio, and glutathione. Activation of the KEAP1/NRF2 axis in LKB1-deficient cells enhanced cell survival and played a critical role in the maintenance of energetic and redox homeostasis in a glutamine-dependent manner. LKB1 and the KEAP1/NRF2 pathways cooperatively drove metabolic reprogramming and enhanced sensitivity to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, these findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma.Significance: In KRAS-mutant non-small cell lung cancer, LKB1 loss results in enhanced energetic/redox stress, which is tolerated, in part, through cooccurring KEAP1/NRF2-dependent metabolic adaptations, thus enhancing glutamine dependence and vulnerability to glutaminase inhibition.