Author:
Zhang Dengyang,He Chunxiao,Guo Yao,Li Jianfeng,Li Bo,Zhao Yuming,Yu Liuting,Chang Zhiguang,Pei Hanzhong,Yang Ming,Li Na,Zhang Qi,He Yulong,Pan Yihang,Zhao Zhizhuang Joe,Zhang Changhua,Chen Yun
Abstract
Abstract
Background
Gastrointestinal stromal tumor (GIST) is a rare type of cancer that occurs in the gastrointestinal tract. The majority of GIST cases carry oncogenic forms of KIT, the receptor for stem cell factor (SCF). Small molecule kinase inhibitor imatinib is effective in prolonging the survival of GIST patients by targeting KIT. However, drug resistance often develops during the therapeutic treatment. Here, we produced a SCF-emtansine drug conjugate (SCF-DM1) with favorable drug efficacy towards GIST cells.
Methods
Recombinant human SCF (rhSCF) was expressed in E. coli cells and further purified with Ni–NTA Sepharose and Phenyl Sepharose. It was then conjugated with DM1, and the conjugated product SCF-DM1 was evaluated using in vitro cell-based assays and in vivo xenograft mouse model.
Results
SCF-DM1 was effective in inhibiting imatinib-sensitive and -resistant GIST cell lines and primary tumor cells, with IC50 values of < 30 nM. It induced apoptosis and cell cycle arrest in GIST cells. In xenograft mouse model, SCF-DM1 showed favorable efficacy and safety profiles.
Conclusions
rhSCF is a convenient and effective vector for drug delivery to KIT positive GIST cells. SCF-DM1 is an effective drug candidate to treat imatinib-sensitive and -resistant GIST.
Funder
Guangdong Provincial Key Laboratory of Digestive Cancer Research
Guangdong Basic and Applied Basic Research Foundation
Publisher
Springer Science and Business Media LLC
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