LKB1基因外显子缺失在肺腺癌EGFR-TKI耐药中的作用和机制研究

Lung cancer is the leading cause of cancer-related death worldwide and lung adenocarcinoma has becoming the predominant pathologic subtype. Epidermal growth factor receptor Tyrosine kinase inhibitor（EGFR-TKI） is one of the main therapeutics for EGFR-mutant lung adenocarcinoma. Previous investigations indicate that solid-predominant subtype and adeno-squamous transition could induce EGFR-TKI insensitivity, while LKB1 exon deletion is closely related to solid subtype formation and adeno-squamous transition and may be the potential molecular mechanism of EGFR-TKI resistance. Current study aims to 1）clarify the clinical and pathologic characteristics of lung adenocarcinoma patients with LKB1 exon deletion; 2)reveal the role of LKB1 exon deletion in solid subtype formation and adeno-squamous transition in formalin-embeded specimens by using micro-dissection and sequencing; 3) investigate the mechanism of LKB1 exon deletion in EGFR-TKI resistance by in vivo and in vitro experiments. This study will reveal the relationship between LKB1 exon deletion and EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma, which could facilitate the development of small molecular agents and followed target therapeutics for patients with lung adenocarcinoma.

肺癌是全球病死率第一位的恶性肿瘤，其中肺腺癌已经成为当前最常见的病理类型。目前，以EGFR突变为靶点的酪氨酸激酶抑制剂（EGFR-TKI）已经成为晚期肺腺癌的主要治疗手段之一。大量研究显示，实体亚型形成及腺-鳞转化可导致EGFR突变型肺腺癌出现EGFR-TKI治疗耐药，LKB1外显子缺失与腺癌实体亚型形成及腺-鳞癌转化密切相关，可能是导致EGFR-TKI耐药的内在分子机制。本研究通过对LKB1基因外显子缺失进行大样本筛选，明确LKB1外显子缺失肺腺癌患者的临床病理及预后特征；并通过显微切割及测序，研究LKB1外显子缺失在实体亚型形成及腺-鳞转化中的作用；最后通过体内及体外实验探索LKB1外显子缺失在介导EGFR-TKI耐药性中的机制。本研究将揭示LKB1外显子缺失在EGFR突变肺腺癌EGFR-TKI耐药中的作用机制，对肺腺癌靶向治疗及特异性小分子抑制剂的开发具有重要参考价值。

肺癌是全球病死率第一位的恶性肿瘤，其中肺腺癌已经成为当前最常见的病理类型。目前，以EGFR突变为靶点的酪氨酸激酶抑制剂（EGFR-TKI）已经成为晚期肺腺癌的主要治疗手段之一。本研究通过对我国大样本肺腺癌进行少见融合基因检测，揭示少见融合基因发生率及其与临床病理特征之间的相关性，以期对肺腺癌靶向治疗提供指导。通过对对NF1突变的肺腺癌进行检测，我们1）明确了NF1突变的预后预测作用；2）NF1突变对EGFR突变型肺腺癌患者靶向治疗的耐药作用；3）NF1/TP53共突变的恶性转化作用；此外，通过对PD-L1进行免疫组化分析，揭示了PD-L1在不同驱动突变背景下的独特分布特点。本研究可为今后临床个体化靶向治疗提供指导。