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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

文献类型：期刊论文

作者Tong, Mengya1,2; Gao, Mingzhao1,2; Xu, Yongping1,2; Fu, Li1,2; Li, Yun1,2; Bao, Xubin1,2; Fu, Haoyu1,2; Quan, Haitian1,2; Lou, Liguang1,2
刊名CANCER SCIENCE
出版日期2019-09-09
页码11
关键词AZD9291 c-Met ADC c-Met overexpression resistance SHR-A1403
ISSN号1347-9032
DOI10.1111/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.
WOS关键词TYROSINE KINASE INHIBITORS ; GENE COPY NUMBER ; ACQUIRED-RESISTANCE ; OSIMERTINIB ; AMPLIFICATION ; GROWTH ; CABOZANTINIB ; MECHANISM ; PATHWAY ; PATIENT
资助项目Science and Technology Commission of Shanghai Municipality[18DZ2293200] ; Yunnan Province Sciences and Technology plan[2017ZF010]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000485498300001
出版者WILEY
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.

入库方式： OAI收割

来源：上海药物研究所

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