Oncotarget

Research Papers:

A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth

Ting Pan, Yiwen Zhang, Nan Zhou, Xin He, Cancan Chen, Liting Liang, Xiaobing Duan, Yingtong Lin, Kang Wu and Hui Zhang _

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Oncotarget. 2016; 7:44299-44309. https://doi.org/10.18632/oncotarget.9996

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Abstract

Ting Pan1,2,3, Yiwen Zhang1,2,3, Nan Zhou1,2,3, Xin He1,2,3, Cancan Chen1,2,3, Liting Liang1,3, Xiaobing Duan1,2, Yingtong Lin1,3, Kang Wu1,2,3, Hui Zhang1,2,3

1Institute of Human Virology, Sun Yat-Sen University, Guangzhou, Guangdong, China

2Key Laboratory of Tropical Diseases Control, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China

3Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China

Correspondence to:

Hui Zhang, email: zhangh92@mail.sysu.edu.cn

Keywords: pancreatic cancer, Vif, Ras binding domain, ubiquitin, KRAS

Received: March 01, 2016     Accepted: June 03, 2016     Published: June 14, 2016

ABSTRACT

Pancreatic cancer is one of the most lethal human diseases, with an all-stage 5-year survival rate below 5%. To date, no effective and specific therapy is available for this disease. Mutations in KRAS are frequently reported in pancreatic and many other cancers; thus, KRAS is an attractive therapeutic target. Our objective was to specifically eliminate mutant KRAS and induce cell death of tumors expressing this mutant protein. We thus constructed several chimeric proteins by connecting the C-terminal domains of several adaptor proteins of E3 ubiquitin ligases such as CBL, CHIP, E6AP, and VHL, as well as VIF encoded by human immunodeficiency virus type 1 (HIV-1), to the Ras binding domain (RBD) of Raf. Although all of these chimeric proteins caused the degradation of mutant KRAS and the death of KRAS-mutant-tumor cell lines, the RBD-VIF with a protein transduction domain (PTD), named PTD-RBD-VIF, had the strongest tumor-killing effect. Intraperitoneally administered recombinant PTD-RBD-VIF potently inhibited the growth of xenografted KRAS-mutant pancreatic cancer cells. Our findings indicate that recombinant PTD-RBD-VIF, a chimeric protein with a combined cellular-viral origin, could be further developed for the treatment of various tumors harboring mutant or over-activated KRAS, especially for cases presenting with pancreatic cancer recurrence after surgery.


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