安罗替尼诱导的 CCL2 减少在非小细胞肺癌治疗中的抗血管生成作用及疗效预测。
Role of anlotinib-induced CCL2 decrease in anti-angiogenesis and response prediction for nonsmall cell lung cancer therapy.
机构信息
Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Central laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Eur Respir J. 2019 Mar 7;53(3). doi: 10.1183/13993003.01562-2018. Print 2019 Mar.
BACKGROUND
Anlotinib has been demonstrated in clinical trials to be effective in prolonging the progression-free survival (PFS) and overall survival (OS) of refractory advanced nonsmall cell lung cancer (NSCLC) patients. However, the underlying molecular mechanisms and predictive biomarkers of anlotinib are still unclear.
METHODS
A retrospective analysis of anlotinib administered to 294 NSCLC patients was performed to screen for underlying biomarkers of anlotinib-responsive patients. Transcriptome and functional assays were performed to understand the antitumour molecular mechanisms of anlotinib. Changes in serum CCL2 levels were analysed to examine the correlation of the anlotinib response between responders and nonresponders.
RESULTS
Anlotinib therapy was beneficial for prolonging OS in NSCLC patients harbouring positive driver gene mutations, especially patients harbouring the epithelial growth factor receptor (EGFR) mutation. Moreover, anlotinib inhibited angiogenesis in an NCI-H1975-derived xenograft model inhibiting CCL2. Finally, anlotinib-induced serum CCL2 level decreases were associated with the benefits of PFS and OS in refractory advanced NSCLC patients.
CONCLUSIONS
Our study reports a novel anti-angiogenesis mechanism of anlotinib inhibiting CCL2 in an NCI-H1975-derived xenograft model and suggests that changes in serum CCL2 levels may be used to monitor and predict clinical outcomes in anlotinib-administered refractory advanced NSCLC patients using third-line therapy or beyond.
背景
临床试验表明，安罗替尼可有效延长难治性晚期非小细胞肺癌（NSCLC）患者的无进展生存期（PFS）和总生存期（OS）。然而，安罗替尼的潜在分子机制和预测生物标志物仍不清楚。
方法
对 294 例接受安罗替尼治疗的 NSCLC 患者进行回顾性分析，以筛选安罗替尼应答患者的潜在生物标志物。进行转录组和功能测定，以了解安罗替尼的抗肿瘤分子机制。分析血清 CCL2 水平的变化，以检查应答者和无应答者之间的安罗替尼反应相关性。
结果
安罗替尼治疗对携带阳性驱动基因突变的 NSCLC 患者的 OS 延长有益，尤其是携带表皮生长因子受体（EGFR）突变的患者。此外，安罗替尼在 NCI-H1975 衍生的异种移植模型中抑制 CCL2 从而抑制血管生成。最后，安罗替尼诱导的血清 CCL2 水平降低与难治性晚期 NSCLC 患者的 PFS 和 OS 获益相关。
结论
我们的研究报告了安罗替尼在 NCI-H1975 衍生的异种移植模型中抑制 CCL2 的新型抗血管生成机制，并表明血清 CCL2 水平的变化可用于监测和预测接受三线或以上治疗的安罗替尼治疗的难治性晚期 NSCLC 患者的临床结局。
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