SHR-A1403, a novel c-mesenchymal-epithelial transition factor (c-Met) antibody-drug conjugate, overcomes AZD9291 resistance in non-small cell lung cancer cells overexpressing c-Met

doi:10.1111/cas.14180

	SHR-A1403, a novel c-mesenchymal-epithelial transition factor (c-Met) antibody-drug conjugate, overcomes AZD9291 resistance in non-small cell lung cancer cells overexpressing c-Met
	Tong, Mengya 1,2; Gao, Mingzhao 1,2; Xu, Yongping 1,2; Fu, Li 1,2; Li, Yun 1,2; Bao, Xubin 1,2; Fu, Haoyu 1,2; Quan, Haitian 1,2; Lou, Liguang 1,2
刊名	CANCER SCIENCE
	2019-09-09
页码	11
关键词	AZD9291 c-Met ADC c-Met overexpression resistance SHR-A1403
ISSN号	1347-9032
DOI	10.1111/cas.14180
通讯作者	Quan, Haitian(haitianquan@simm.ac.cn) ; Lou, Liguang(lglou@simm.ac.cn)
英文摘要	Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as the first-line treatment of non-small cell lung cancers (NSCLC) harboring EGFR-activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the EGFR-TKI, AZD9291, in NSCLC cells using SHR-A1403, a novel c-mesenchymal-epithelial transition factor (c-Met)-targeting antibody-drug conjugate (ADC) consisting of an anti-c-Met monoclonal antibody (c-Met mAb) conjugated to a microtubule inhibitor. Resistant cells were established by exposing HCC827 to increasing concentrations of EGFR-TKI. c-Met was found to be overexpressed in most resistant cells. AZD9291 resistance was partially restored by combination of AZD9291 and crizotinib only in resistant cells overexpressing phospho-c-Met, which synergistically inhibited c-Met-mediated phosphorylation of the downstream targets ERK1/2 and AKT. In resistant cells overexpressing c-Met, neither crizotinib nor c-Met mAb was able to overcome AZD9291 resistance. In contrast, SHR-A1403 strongly inhibited proliferation of AZD9291-resistant HCC827 overexpressing c-Met, regardless of the levels of c-Met phosphorylation. SHR-A1403 bound to resistant cells overexpressing c-Met was internalized into cells and released associated microtubule inhibitor, resulting in cell-killing activity that was dependent on c-Met expression levels only, irrespective of the involvement of c-Met or EGFR signaling in AZD9291 resistance. Consistent with its activity in vitro, SHR-A1403 significantly inhibited the growth of AZD9291-resistant HCC827 tumors and caused tumor regression in vivo. Thus, our findings show that SHR-A1403 efficiently overcomes AZD9291 resistance in cells overexpressing c-Met, and further indicate that c-Met expression level is a biomarker predictive of SHR-A1403 efficacy.
资助项目	Science and Technology Commission of Shanghai Municipality[18DZ2293200] ; Yunnan Province Sciences and Technology plan[2017ZF010]
WOS关键词	TYROSINE KINASE INHIBITORS ; GENE COPY NUMBER ; ACQUIRED-RESISTANCE ; OSIMERTINIB ; AMPLIFICATION ; GROWTH ; CABOZANTINIB ; MECHANISM ; PATHWAY ; PATIENT
WOS研究方向	Oncology
语种	英语
出版者	WILEY
WOS记录号	WOS:000485498300001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288598]
专题	中国科学院上海药物研究所
通讯作者	Quan, Haitian; Lou, Liguang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Tong, Mengya,Gao, Mingzhao,Xu, Yongping,et al. SHR-A1403, a novel c-mesenchymal-epithelial transition factor (c-Met) antibody-drug conjugate, overcomes AZD9291 resistance in non-small cell lung cancer cells overexpressing c-Met[J]. CANCER SCIENCE,2019:11.
APA	Tong, Mengya.,Gao, Mingzhao.,Xu, Yongping.,Fu, Li.,Li, Yun.,...&Lou, Liguang.(2019).SHR-A1403, a novel c-mesenchymal-epithelial transition factor (c-Met) antibody-drug conjugate, overcomes AZD9291 resistance in non-small cell lung cancer cells overexpressing c-Met.CANCER SCIENCE,11.
MLA	Tong, Mengya,et al."SHR-A1403, a novel c-mesenchymal-epithelial transition factor (c-Met) antibody-drug conjugate, overcomes AZD9291 resistance in non-small cell lung cancer cells overexpressing c-Met".CANCER SCIENCE (2019):11.