Targeted Degradation of KRAS by an Engineered Ubiquitin Ligase Suppresses Pancreatic Cancer Cell Growth In Vitro and In Vivo
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Abstract
KRAS is an attractive pancreatic ductal adenocarcinoma (PDAC) therapeutic target. E3 ligase is thought to be the component of the ubiquitin conjugation system that is directly responsible for substrate recognition. In this study, an engineered E3 ubiquitin ligase (RC-U) was generated to target the KRAS oncoprotein for ubiquitination and degradation. The engineered E3 ubiquitin ligases (RC-U) were constructed (pRC-U and lentivirus-expressing RC-U). After transfecting the pRC-U plasmid into human pancreatic cancer cells, KRAS expression levels were determined. KRAS expression was also evaluated in cells transfected with pRC-U and treated with MG-132 or cycloheximide. Interactions between RC-U and KRAS as well as whether RC-U could ubiquitinate KRAS were investigated. Extracellular signal–regulated kinase 1/2 (ERK1/2) and phosphorylated ERK 1/2 (pERK1/2) levels were examined in pancreatic cancer cells transfected with pRC-U. The effects of RC-U on pancreatic cancer cell growth were assessed. RC-U decreased KRAS protein levels. After pRC-U transfection, KRAS stability was increased in the presence of MG-132. HEK 293T cells were transfected with a mutant KRAS construct together with pRC-U and incubated with cycloheximide to inhibit new protein synthesis. The exogenous mutant KRAS oncoprotein was degraded more quickly. RC-U can bind KRAS and KRAS can be ubiquitinated by RC-U. pERK1/2 protein levels were decreased. RC-U resulted in reduced cell proliferation in vitro and in vivo. KRAS destruction by RC-U occurred through a ubiquitin-dependent, proteasome-mediated degradation pathway. RC-U inhibited pancreatic cancer cell growth in vitro and in vivo. Mol Cancer Ther; 12(3); 286–94. ©2012 AACR.
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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 [16]
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- Authors
- Ma, Y., Gu, Y., Zhang, Q., Han, Y., Yu, S., Lu, Z., & Chen, J.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Authors' Affiliations: 1Department of Pathology, Peking Union Medical College Hospital; 2National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing; 3Department of Pathology, Zhengzhou University, Affiliated Hospital 1, Zhengzhou, PR China; and 4Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina
- Corresponding author
- Chen, Jie
- Venue
- Molecular Cancer Therapeutics
- Published
- 2013-03-01
- Volume
- 12
- Issue
- 3
- Pages
- 286-294
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2120917886
- Cited by
- 55
- References
- 49
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 3 · 2015: 8 · 2014: 5
- FWCI
- 2.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30471970)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- KRAS, pancreatic ductal adenocarcinoma, targeted protein degradation, ubiquitination, proteasomal degradation, ERK1/2 phosphorylation, cell proliferation inhibition, pancreatic cancer treatment
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Humans, Pancreatic Neoplasms, Phosphorylation, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Cell Proliferation, Mice, HEK293 Cells, Molecular Targeted Therapy, Proteolysis
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