Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC.
Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC.
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趋化因子介导的血管生成在抗克唑替尼及其在EML4-ALK阳性NSCLC中的抗性中的作用。
DOI：
10.1186/s12967-022-03451-2
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发表时间：
2022-05-31
影响因子：
7.4
通讯作者：
Han X
中科院分区：
文献类型：
--
作者：
Wang S;Lou N;Luo R;Hao X;Liu Y;Wang L;Shi Y;Han X
识别临床结局和耐药性的早期血浆生物标志物对于间变性淋巴瘤激酶（ALK）阳性晚期非小细胞肺癌（NSCLC）患者的风险分层至关重要。此外，抗血管生成药物安洛替尼能否逆转ALK-酪氨酸激酶抑制剂（ALK-TKI）克唑替尼的耐药性尚不清楚，也没有研究探讨安洛替尼联合克唑替尼对ALK阳性患者的疗效。本研究采用Luminex液体悬浮芯片分析了61例接受克唑替尼治疗的ALK阳性NSCLC患者的76份基线和纵向血浆样本中的40种趋化因子。使用RNA序列（RNA-seq）鉴定H3122和H3122-克唑替尼耐药（H3122 CR）细胞之间的差异表达基因（DEG）。试管形成试验用于研究趋化因子对血管生成的影响。建立H3122 CR异种移植瘤模型，验证安洛替尼联合克唑替尼的体内有效性和安全性。基线和进展血浆样本检测表明，CCL 20在监测和预测克唑替尼的临床应答方面发挥了关键作用（无进展生存期风险比：2.27（1.13-4.58）;总生存期风险比：2.7（1.23-5.8））。H3122和H3122 CR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，CCL 20可能通过JAK 2/STAT 3-CCL 20-VEGFA/IL 6轴激活血管生成而诱导克唑替尼耐药。我们进一步发现，抗血管生成TKI安洛替尼可通过抑制趋化因子诱导的血管生成来逆转克唑替尼耐药，安洛替尼与克唑替尼联合使用在体内外均具有比单药治疗更好的抗肿瘤效果。总体而言，CCL 20介导的血管生成与克唑替尼耐药有关，可通过在EML 4-ALK阳性NSCLC中使用安洛替尼克服。安洛替尼和克唑替尼联合治疗是治疗ALK-TKI耐药患者的一种有前景的策略。在线版本包含补充材料，可通过10.1186/s12967-022-03451-2获取。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s12967-022-03451-2.
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[在ALK阳性非小细胞肺癌中靶向治疗的耐药性机制和预后标记的进展]。
DOI：
10.3779/j.issn.1009-3419.2020.101.44
发表时间：
2020-11-20
期刊：
Zhongguo fei ai za zhi = Chinese journal of lung cancer
影响因子：
--
作者：
Wang S;Shi Y;Han X
通讯作者：
Han X
DOI：
10.1200/jco.2017.76.2294
发表时间：
2018-04-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Lin JJ;Zhu VW;Yoda S;Yeap BY;Schrock AB;Dagogo-Jack I;Jessop NA;Jiang GY;Le LP;Gowen K;Stephens PJ;Ross JS;Ali SM;Miller VA;Johnson ML;Lovly CM;Hata AN;Gainor JF;Iafrate AJ;Shaw AT;Ou SI
通讯作者：
Ou SI
影响因子：
5.7
作者：
Watanabe H;Ichihara E;Kayatani H;Makimoto G;Ninomiya K;Nishii K;Higo H;Ando C;Okawa S;Nakasuka T;Kano H;Hara N;Hirabae A;Kato Y;Ninomiya T;Kubo T;Rai K;Ohashi K;Hotta K;Tabata M;Maeda Y;Kiura K
通讯作者：
Kiura K
影响因子：
9.7
作者：
Wang, Gui-Zhen;Cheng, Xin;Zhou, Guang-Biao
通讯作者：
Zhou, Guang-Biao
影响因子：
11.2
作者：
Pailler, Emma;Oulhen, Marianne;Farace, Francoise
通讯作者：
Farace, Francoise