KEAP1-NRF2突变肺癌的分子分型和靶向治疗研究

Somatic mutations in KEAP1 and NRF2 genes have been observed in over 20% of patients with non-small cell lung cancer (NSCLC), which serve as a crucial cytoprotective machinery to support the malignant progression. However, whether KEAP1-NRF2 mutant lung cancer defines a molecularly uniform or heterogeneous disease, and how therapeutic intervention can be applied to rationally control NRF2-dependent oncogenesis remain largely unresolved. We have found that KEAP1-NRF2 mutant lung cancer exhibited unique characteristics of antioxidative stress, reactive oxygen species metabolism, patient prognosis and immune activities. KEAP1-NRF2 mutant lung adenocarcinoma could be stratified into three molecular subtypes and KEAP1-NRF2 mutant lung squamous cell carcinoma could be classified into two molecular subtypes, each displaying distinct immune features. Based on these findings, we propose the current project to identify molecular targeted therapies for KEAP1-NRF2 mutant lung cancer, further investigate the genomic and clinicopathological attributes of different subtypes and determine the gene signatures that define molecular subtypes. These studies will improve our understanding of KEAP1-NRF2 mutant lung cancer, develop subtyping system for mutated tumors and reveal potential therapeutic strategies against this deadly disease.

最近KEAP1-NRF通路基因被发现在非小细胞肺癌中突变率较高，并被推测在肺癌发生和发展过程中可能具有重要功能，但对其分子病理特征及相关治疗方法目前缺乏进一步研究。本项目预实验提示该基因突变与氧化应激反应、活性氧代谢、病人预后及免疫活性相关，KEAP1-NRF2突变肺腺癌包括三个分子亚型，KEAP1-NRF2突变肺鳞癌包括两个分子亚型，不同分子亚型显示出不同的免疫特性。本课题将在预实验的基础上，进一步通过高通量药物筛选寻找可用于KEAP1-NRF2突变肺癌的靶向治疗药物，研究KEAP1-NRF2突变肺癌分子亚型的遗传及临床特点，构建KEAP1-NRF2突变肺癌分子亚型的基因标记，并分析突变肺癌的免疫特性。这些研究旨在探讨KEAP1-NRF2突变型肺癌的分子分型和治疗方法，从而为临床决策提供新思路。

非小细胞肺癌中体细胞KEAP1-NRF2通路突变是一种较为常见的突变类型。但KEAP1/NRF2突变型肺癌的生物学特性和分子亚型尚不明确，且该突变的治疗意义仍不清楚。本研究对原发性肿瘤和含有KEAP1或NFE2L2（编码NRF2）基因突变的癌细胞系进行了逐步、综合的分析并结合临床患者样本测序，发现KEAP1/NRF2突变型肺癌呈现APOBEC介导的突变特征，肿瘤血管生成受损，低氧应激升高和免疫细胞浸润不足。基于基因表达的亚型分析揭示了KEAP1/NRF2突变型肺腺癌的三个分子亚群和KEAP1/NRF2突变型肺鳞癌的两个分子亚群，不同亚群的遗传、分化、免疫学和临床病理学特性有差异。此外，患者标本测序提示KEAP1/NRF2少与其他驱动基因合并出现且可能提示治疗预后不佳。我们的数据表明KEAP1/NRF2突变型肺癌是一种微环境独特、生物异质性和临床低估的疾病。这些研究将增加我们对该突变同路的认识从而建立以KEAP1/NRF2通路为分子靶点的理论基础，有助于开发以KEAP1-NRF2通路激活为特征的恶性肿瘤的新靶向治疗策略。