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LKB1(liver kinase B1)调控细胞增殖和细胞代谢。在非小细胞肺癌发病过程中,缺失LKB1的肿瘤细胞如何协调快速增殖和代谢应激这一矛盾目前尚不清楚。在该研究中,利用KrasG12D;Lkb1lox/lox(KL)小鼠模拟缺失LKB1的非小细胞肺癌的发病过程,发现KL肺腺癌和鳞癌具有不同的氧化还原水平,且活性氧簇(reactive oxygen species,ROS)可以调控肺腺癌向肺鳞癌的转分化过程。进一步的研究发现,肺腺癌中氧化还原态失衡源于戊糖磷酸途径的失调和受AMPK-ACC信号轴调控的脂肪酸氧化通路的失活。有趣的是,类似的肿瘤异质性和氧化还原异质性同样存在于LKB1失活的临床肺癌样本中。在KL小鼠中进行临床前药理学研究发现,一部分肺腺癌可以通过转分化为肺鳞癌逃脱靶向细胞代谢的药物作用并获得耐药性。该研究揭示了氧化还原调控缺失LKB1的非小细胞肺癌可塑性以及药物响应的重要作用。
LKB1 (liver kinase B1) regulates cell proliferation and cell metabolism. In the pathogenesis of non-small cell lung cancer, the lack of LKB1 tumor cells how to coordinate the rapid proliferation and metabolic stress contradictions is not yet clear. In this study, KrasG12D; Lkb1lox / lox (KL) mice were used to model the pathogenesis of LKB1-deficient non-small cell lung cancer and found that KL lung adenocarcinoma and squamous cell carcinoma have different redox levels and that reactive oxygen species species, ROS) can regulate the transdifferentiation of lung adenocarcinoma to lung squamous cell carcinoma. Further studies have found that the redox imbalance in lung adenocarcinomas results from the imbalance of the pentose phosphate pathway and the inactivation of fatty acid oxidation pathways regulated by the AMPK-ACC signal axis. Interestingly, similar tumor heterogeneity and redox heterogeneity are also present in LKBl-inactivated clinical lung cancer samples. A preclinical pharmacology study in KL mice found that a subset of lung adenocarcinomas can escape drug-induced cell-targeting and transresistance by transdifferentiation into squamous lung carcinomas. This study revealed the important role of redox regulation of LKB1-deficient non-small cell lung cancer plasticity and drug response.