Third-generation EGFR inhibitor HS-10296 in combination with famitinib, a multi-targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR-mutant non-small cell lung cancer cells

doi:10.1111/1759-7714.13902

	Third-generation EGFR inhibitor HS-10296 in combination with famitinib, a multi-targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR-mutant non-small cell lung cancer cells
	Zhang, Mi 1,2; Quan, Haitian 1; Fu, Li 1; Li, Yun 1; Fu, Haoyu 1; Lou, Liguang 1
刊名	THORACIC CANCER
	2021-03-03
页码	9
关键词	EGFR‐ mutant non‐ small cell lung cancer famitinib HS‐ 10296 multi‐ targeted tyrosine kinase inhibitor third‐ generation EGFR inhibitor
ISSN号	1759-7706
DOI	10.1111/1759-7714.13902
通讯作者	Lou, Liguang(lglou@simm.ac.cn)
英文摘要	Background As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. Methods The combined antitumor effects of HS-10296, a third-generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non-small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies. Results Famitinib strengthened the effects of HS-10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS-10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS-10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS-10296 and famitinib exerted synergistic antitumor activity in NCI-H1975 and PC-9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues. Conclusions Collectively, our results indicate that HS-10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third-generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR-mutant NSCLC.
资助项目	Science and Technology Commission of Shanghai Municipality[18DZ2293200] ; Yunnan Province Sciences and Technology plan[2017ZF010]
WOS关键词	GROWTH
WOS研究方向	Oncology ; Respiratory System
语种	英语
出版者	WILEY
WOS记录号	WOS:000624542500001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295517]
专题	中国科学院上海药物研究所
通讯作者	Lou, Liguang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Shanghai Univ, Sch Life Sci, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Mi,Quan, Haitian,Fu, Li,et al. Third-generation EGFR inhibitor HS-10296 in combination with famitinib, a multi-targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR-mutant non-small cell lung cancer cells[J]. THORACIC CANCER,2021:9.
APA	Zhang, Mi,Quan, Haitian,Fu, Li,Li, Yun,Fu, Haoyu,&Lou, Liguang.(2021).Third-generation EGFR inhibitor HS-10296 in combination with famitinib, a multi-targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR-mutant non-small cell lung cancer cells.THORACIC CANCER,9.
MLA	Zhang, Mi,et al."Third-generation EGFR inhibitor HS-10296 in combination with famitinib, a multi-targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR-mutant non-small cell lung cancer cells".THORACIC CANCER (2021):9.