肺腺癌肿瘤异质性在EGFR-TKI耐药中的作用和机制研究

项目名称： 肺腺癌肿瘤异质性在EGFR-TKI耐药中的作用和机制研究

项目编号： No.81330056

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 陈海泉

作者单位： 复旦大学

项目金额： 290万元

中文摘要： 表皮生长因子受体（EGFR）突变是东亚肺腺癌最常见的驱动基因突变之一，以其为靶点的酪氨酸激酶抑制剂（TKI）在临床获得了巨大成功，但绝大多数患者最终将发生耐药并导致治疗失败。目前研究显示肿瘤具有亚克隆异质性，EGFR-TKI敏感亚克隆在药物作用下被大量杀灭，但耐药亚克隆则持续发展引起耐药和肿瘤的进展。我们通过对显微切割样本的分析，初步对药物敏感性与亚克隆异质性的关联进行了阐述，通过大规模文库筛选确定了与EGFR-TKI治疗抵抗的主要相关基因。在此基础上，本项目将进一步研究肺腺癌EGFR-TKI治疗敏感/耐受异质性亚克隆产生的内在机制，研究这些耐药基因异常在肿瘤组织中的分布，同时通过耐药细胞株，建立模拟肿瘤内异质性的细胞模型，预测EGFR-TKI疗效。这将有望革新我们对肿瘤异质性在耐药中作用的认知，推动针对异质性耐药的临床试验开展，以期提高肺癌的整体诊治水平。

中文关键词： 异质性;肺腺癌;表皮生长因子;耐药;

英文摘要： Mutational activation of epidermal growth factor receptor(EGFR) is the most prevalent genetic alteration in non-small cell lung cancer (NSCLC) of East Asian population. Moreover, the marked tumor regression and improved survival of advanced EGFR-mutated lung cancer patients in response to treatment with EGFR tyrosine kinase inhibitors(EGFR TKI) demonstrated the essential role of EGFR in lung cancers. However,resistance to EGFR TKI treatment invariably occurs, and there is no effective therapy for patients who develop such resistance..Recent studies have identified extensive heterogeneity in tumors using large-scale sequencing and single cell analyses. Intratumor heterogeneity arises through the evolution of genetically diverse subclones varying in proliferation, persistence, and drug tolerance. Thereby chemotherapeutic agents or targeted drugs, such as EGFR-TKI, could destroy the sensitive clones but promote the dominance of previously insensitive lineages. We previously analyzed adenosquamous cell lung cancer tissues by microdissection technique, and found that discrepancy of driver mutations between the adeno and squamous component frequently occurred. We also identified the major mechanisms associated with EGFR-TKI resistance by large scale library screening. This finding further indicated our current hypothesis that therapy sensitivity is associated with subclonal heterogeneity..In this study, we further investigate the mechanism of development of EGFR-TKI sesitive/resistant subclones. Then we will analyze whether those genetic alterations related to EGFR TKI resistance exist in multiple spatially surgically resected samples obtained from prmary lung tumors by direct sequencing, chromosome aberration analysis and immunohistochemical analysis. In addition, we will also construct a heterogeneous mixture of EGFR-TKIs resistant and sensitizing lung cancer cell model. With this evolutionary model, we will predict alternative therapeutic strategies for drug-resistant lung cancers. We will also explore the genetic changes associated with resistance to EGFR TKIs at a single-cell nucleotide level. Our study may contribute to overcoming the resistance of EGFR TKIs to achieve curative therapy for EGFR mutant lung cancer patients， and improve our management of lung adenocarcinoma.

英文关键词： heterogeneity;lung adenocarcinoma;epidermal growth factor recept;resistance