趋化因子介导的血管生成在 EML4-ALK 阳性 NSCLC 中对抗克唑替尼的耐药中的作用及其被安罗替尼逆转。
Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC.
机构信息
Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
出版信息
J Transl Med. 2022 May 31;20(1):248. doi: 10.1186/s12967-022-03451-2.
BACKGROUND
The identification of early plasma biomarkers for clinical outcomes and drug resistance has key importance for risk stratification in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients. Moreover, it remains unclear whether the anti-angiogenic drug anlotinib can reverse the resistance of ALK-tyrosine kinase inhibitor (ALK-TKI) crizotinib, and no research has explored the effect of anlotinib combined with crizotinib on ALK-positive patients.
METHODS
In this study, 76 baseline and longitudinal plasma samples from 61 ALK-positive NSCLC patients receiving crizotinib treatment were analyzed by Luminex liquid suspension chip for 40 chemokines. RNA sequence (RNA-seq) was used to identify differentially expressed genes (DEGs) between H3122 and H3122-crizotinib resistant (H3122CR) cells. Tube formation assay was performed to investigate the effect of chemokines on angiogenesis. And H3122CR-derived xenograft model was constructed to validate the efficacy and safety of anlotinib combined with crizotinib in vivo.
RESULTS
Baseline and progression plasma samples detection suggested that CCL20 played a crucial role in monitoring and predicting the clinical response of crizotinib (hazard ratio for progression-free survival: 2.27 (1.13-4.58); for overall survival: 2.7 (1.23-5.8)). RNA-seq results for H3122 and H3122CR cells showed that high expression of chemokines and angiogenesis pathways were involved in crizotinib resistance. Subsequently, in vitro experiments indicated that CCL20 may induce crizotinib resistance by activation of angiogenesis via JAK2/STAT3-CCL20-VEGFA/IL6 axis. We further found that anti-angiogenic TKI anlotinib could reverse crizotinib resistance by inhibiting chemokines-induced angiogenesis, and anlotinib combined with crizotinib has a better antitumor effect than monotherapy in vitro & in vivo.
CONCLUSIONS
Overall, CCL20-mediated angiogenesis is involved in crizotinib resistance and could be overcome by using anlotinib in EML4-ALK positive NSCLC. The combination of anlotinib and crizotinib is a promising strategy for patients resistant to ALK-TKIs.
背景
对于间变性淋巴瘤激酶（ALK）阳性晚期非小细胞肺癌（NSCLC）患者的风险分层，鉴定早期血浆生物标志物对临床结局和耐药性具有重要意义。此外，抗血管生成药物安罗替尼是否能逆转 ALK-酪氨酸激酶抑制剂（ALK-TKI）克唑替尼的耐药性尚不清楚，也没有研究探讨安罗替尼联合克唑替尼对 ALK 阳性患者的影响。
方法
本研究通过 Luminex 液相悬浮芯片分析了 61 例接受克唑替尼治疗的 ALK 阳性 NSCLC 患者的 76 例基线和纵向血浆样本，检测了 40 种趋化因子。使用 RNA 测序（RNA-seq）鉴定 H3122 和 H3122-克唑替尼耐药（H3122CR）细胞之间差异表达的基因（DEGs）。管形成试验用于研究趋化因子对血管生成的影响。构建 H3122CR 衍生的异种移植模型，以验证安罗替尼联合克唑替尼在体内的疗效和安全性。
结果
基线和进展期血浆样本检测提示 CCL20 在监测和预测克唑替尼的临床反应中起着关键作用（无进展生存期的危险比：2.27（1.13-4.58）；总生存期：2.7（1.23-5.8））。H3122 和 H3122CR 细胞的 RNA-seq 结果表明，趋化因子和血管生成途径的高表达参与了克唑替尼耐药。随后，体外实验表明 CCL20 可能通过 JAK2/STAT3-CCL20-VEGFA/IL6 轴激活血管生成诱导克唑替尼耐药。我们进一步发现，抗血管生成 TKI 安罗替尼可以通过抑制趋化因子诱导的血管生成来逆转克唑替尼耐药，并且安罗替尼联合克唑替尼在体外和体内的抗肿瘤效果优于单药治疗。
结论
总的来说，CCL20 介导的血管生成参与了克唑替尼耐药，在 EML4-ALK 阳性 NSCLC 中使用安罗替尼可以克服这种耐药性。安罗替尼和克唑替尼的联合是克服 ALK-TKIs 耐药患者的一种有前途的策略。
Zotero 插件