Combined inhibition of MET and VEGF enhances therapeutic efficacy of EGFR TKIs in EGFR-mutant non-small cell lung cancer with concomitant aberrant MET activation

吉非替尼 癌症研究 表皮生长因子受体 MAPK/ERK通路 克里唑蒂尼 表皮生长因子受体抑制剂 血管内皮生长因子 肺癌 酪氨酸激酶抑制剂 酪氨酸激酶 信号转导 生物 癌症 医学 细胞生物学 内科学 血管内皮生长因子受体 恶性胸腔积液
作者
Shanshan Huang,Yaling Long,Yuan Gao,Wanling Lin,Wenxin Wang,Jizong Jiang,Xun Yuan,Yuan Chen,Peng Zhang,Qian Chu
出处
期刊:Experimental hematology & oncology [Springer Nature]
卷期号:13 (1)
标识
DOI:10.1186/s40164-024-00565-9
摘要

Abstract Background Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR -mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined. Methods The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo. Results We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR / MET co-altered case. Conclusions Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
sugar完成签到,获得积分10
1秒前
细心慕凝完成签到 ,获得积分10
2秒前
站起来蹬是不对的完成签到,获得积分10
7秒前
背完单词好睡觉完成签到 ,获得积分10
8秒前
毛毛发布了新的文献求助10
9秒前
ZZ完成签到 ,获得积分10
10秒前
10秒前
优秀尔芙发布了新的文献求助10
11秒前
12秒前
上官若男应助袁大头采纳,获得10
13秒前
顾北发布了新的文献求助10
15秒前
激情的丹寒应助damai采纳,获得10
17秒前
18秒前
925完成签到,获得积分10
18秒前
cossen发布了新的文献求助10
21秒前
顾北完成签到,获得积分10
23秒前
深情安青应助一杯美事采纳,获得10
24秒前
Owen应助袁大头采纳,获得10
24秒前
24秒前
27秒前
ding应助南吕采纳,获得10
27秒前
moon完成签到 ,获得积分10
29秒前
Dore完成签到,获得积分20
32秒前
32秒前
33秒前
YY发布了新的文献求助10
33秒前
34秒前
34秒前
chant完成签到 ,获得积分10
34秒前
毛毛完成签到,获得积分10
35秒前
一杯美事发布了新的文献求助10
39秒前
42秒前
管理想完成签到,获得积分10
43秒前
Kelvin.Tsi完成签到 ,获得积分10
44秒前
46秒前
xuan完成签到,获得积分20
52秒前
52秒前
灰色与青完成签到,获得积分10
55秒前
淡定的傲玉完成签到 ,获得积分10
55秒前
橘仔乐完成签到,获得积分10
56秒前
高分求助中
The Oxford Handbook of Social Cognition (Second Edition, 2024) 1050
Kinetics of the Esterification Between 2-[(4-hydroxybutoxy)carbonyl] Benzoic Acid with 1,4-Butanediol: Tetrabutyl Orthotitanate as Catalyst 1000
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
Handbook of Qualitative Cross-Cultural Research Methods 600
Chen Hansheng: China’s Last Romantic Revolutionary 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3140334
求助须知:如何正确求助?哪些是违规求助? 2791068
关于积分的说明 7797887
捐赠科研通 2447569
什么是DOI,文献DOI怎么找? 1301942
科研通“疑难数据库(出版商)”最低求助积分说明 626345
版权声明 601194