LKB1在非小细胞肺癌可塑性及耐药反应中的重要作用及机制

The Essential Role and Related Mechanism of LKB1 in Regulating Non-small Cell Lung Cancer Plasticity and Drug Resistance

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 both cell growth and energy metabolism. It remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in non-small cell lung cancer（NSCLC）. Here in KrasG12D;Lkb1lox/lox（KL） mouse model, we reveal differential reactive oxygen species（ROS） levels in lung adenocarcinoma（ADC） and squamous cell carcinoma（SCC）. ROS can modulate ADC-to-SCC transdifferentiation（AST）. Further, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Interestingly, similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials towards metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation. This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC.