Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line
Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line
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DOI：
10.3389/fonc.2019.00886
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发表时间：
2019-09-11
影响因子：
4.7
通讯作者：
Han, Baohui
中科院分区：
文献类型：
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作者：
Lu, Jun;Shi, Qin;Han, Baohui
口服多靶点酪氨酸激酶抑制剂（TKI） anlotinib在三线临床试验中对非小细胞肺癌（NSCLC）有效。然而，一小部分患者仍然无反应，这就需要如何识别对安洛替尼有反应的患者。在本研究中，我们的目的是通过整合转录组分析筛选潜在的生物标志物，用于anlotinib应答分层。与anlotinib敏感肺癌细胞NCI-H1975比较，我们发现在anlotinib耐药NCI-H1975细胞中有1315个基因差异表达。在丰富的血管生成相关基因中，我们通过TCGA队列的Kaplan-Meier生存分析发现，高表达的KLK5和L1CAM与NSCLC患者的临床预后差相关。此外，在ALTER0303 （NCT02388919）队列中的一项独立验证表明，高血清水平的KLK5和L1CAM也与三线非小细胞肺癌患者的不良安洛替尼反应相关。最后，我们证明了在耐安洛替尼的NCI-H1975细胞中，敲低KLK5和L1CAM会增加安洛替尼诱导的细胞毒性。总之，我们的研究表明，血清KLK5和L1CAM水平可能作为三线非小细胞肺癌患者安洛替尼反应性分层的生物标志物。
The oral multi-targeted tyrosine kinase inhibitor (TKI) anlotinib is effective for non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, a fraction of patients remains non-responsive, raising the need of how to identify anlotinib-responsive patients. In the present study, we aimed to screen potential biomarkers for anlotinib-responsive stratification via integrated transcriptome analysis. Comparing with the anlotinib-sensitive lung cancer cell NCI-H1975, we found 1,315 genes were differentially expressed in anlotinib-resistant NCI-H1975 cells. Among the enriched angiogenesis-related genes, we observed high expression of KLK5 and L1CAM was mostly associated with poor clinical outcomes in NSCLC patients through Kaplan-Meier survival analysis in a TCGA cohort. Moreover, an independent validation in a cohort of ALTER0303 (NCT02388919) indicated that high serum levels of KLK5 and L1CAM were also associated with poor anlotinib response in NSCLC patients at 3rd line. Lastly, we demonstrated that knockdown of KLK5 and L1CAM increases anlotinib-induced cytotoxicity in anlotinib-resistant NCI-H1975 cells. Collectively, our study suggested serum levels of KLK5 and L1CAM potentially serve as biomarkers for anlotinib-responsive stratification in NSCLC patients at 3rd line.