A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth
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// Ting Pan 1, 2, 3 , Yiwen Zhang 1, 2, 3 , Nan Zhou 1, 2, 3 , Xin He 1, 2, 3 , Cancan Chen 1, 2, 3 , Liting Liang 1, 3 , Xiaobing Duan 1, 2 , Yingtong Lin 1, 3 , Kang Wu 1, 2, 3 , Hui Zhang 1, 2, 3 1 Institute of Human Virology, Sun Yat-Sen University, Guangzhou, Guangdong, China 2 Key Laboratory of Tropical Diseases Control, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China 3 Guangdong 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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In mice bearing xenograft pancreatic tumours, orthotopic injection of the Vif-based degrader was more efficacious than intraperitoneal injection, highlighting the need for better delivery methods to advance bioPROTACs from laboratory tools to therapeutics.
“However, in mice bearing xenograft pancreatic tumours, orthotopic injection of the Vif-based degrader was more efficacious than intraperitoneal injection, highlighting the need for better delivery methods to advance bioPROTACs from laboratory tools to therapeutics.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [212]
Other groups have reported fusion bioPROTACs that degraded HER2, MYC and KRAS and demonstrated therapeutically relevant effects in human cancer cell lines and mouse xenograft tumour models overexpressing these POIs.
“Since then, other groups have reported fusion bioPROTACs that degraded the cancer targets human epidermal growth factor receptor 2 (HER2), MYC and KRAS and demonstrated therapeutically relevant effects in human cancer cell lines and mouse xenograft tumour models overexpressing these POIs16,17,211,212.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [212]
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- Authors
- Pan, T., Zhang, Y., Zhou, N., He, X., Chen, C., Liang, L., Duan, X., Lin, Y., Wu, K., & Zhang, H.
- Affiliations
- Sun Yat-sen University (CN)
- Corresponding author
- Zhang, Yiwen
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2016-06-14
- Volume
- 7
- Issue
- 28
- Pages
- 44299-44309
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5190097
- OpenAlex
- W2442635747
- Cited by
- 21
- References
- 54
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 1 · 2020: 3 · 2018: 1
- FWCI
- 0.18
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (2009010058, 301500740)
- China Postdoctoral Science Foundation
- Natural Science Foundation of Guangdong Province (2015A030310442, 2009010058)
- Guangdong Province Introduction of Innovative R&D Team (2009010058, No. 2009010058)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Keywords
- mutant KRAS, pancreatic cancer, fusion protein, Vif, Ras-binding domain, Raf, E3 ubiquitin ligase, protein degradation, cell-penetrating peptides, tumor growth inhibition, xenografts, targeted cancer therapy, HIV-1 Vif, CBL, CHIP, UBE3A, VHL, apoptosis, cancer cell death, ubiquitination
- MeSH terms
- Animals, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Pancreatic Neoplasms, Recombinant Fusion Proteins, Signal Transduction, Proto-Oncogene Proteins p21(ras), Xenograft Model Antitumor Assays, Ubiquitin-Protein Ligases, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Ubiquitination, HEK293 Cells
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