USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer
Open accessAbstract
Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.
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Studies of the iKras mouse model have highlighted mechanisms to enable bypass of oncogenic KRAS addiction, including adoption of a KRAS-independent cell state dependent on oxidative phosphorylation, induction of SMARCB-MYC-network-driven mesenchymal reprogramming, activation of the TGFβ-SMAD3/4 axis via TME remodeling, and USP21-mediated upregulation of macropinocytosis.
“Furthermore, studies of the iKras mouse model have highlighted myriad mechanisms to enable bypass of oncogenic KRAS addiction, including the adoption of a KRAS-independent cell state dependent on oxidative phosphorylation (5), induction of SMARCB–MYC-network-driven mesenchymal reprogramming (38), activation of the TGFβ-SMAD3/4 axis via TME remodeling (39), and USP21-mediated upregulation of macrop”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [40]
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Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer
Dilly, J., Hoffman, M. T., Abbassi, L., Li, Z., Paradiso, F., Parent, B. D., Hennessey, C. J., Jordan, A. C., Morgado, M., Dasgupta, S., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0177 · Cited by 276 · see citing works
“…including the adoption of a KRAS-independent cell state dependent on oxidative phosphorylation (5), induction of SMARCB–MYC-network-driven mesenchymal reprogramming (38), activation of the TGF β - SMAD3/4 axis via TME remodeling (39), and USP21-mediated upregulation of macropinocytosis (40).”
Background
- Authors
- Hou, P., Ma, X., Yang, Z., Zhang, Q., Wu, C.-J., Li, J., Tan, L., Yao, W., Yan, L., Zhou, X., Kimmelman, A. C., Lorenzi, P. L., Zhang, J., Jiang, S., Spring, D., Wang, Y. A., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Jilin University (CN)
- NYU Langone Health (US)
- Corresponding author
- Wang, Y. Alan
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2021-09-16
- Volume
- 35
- Issue
- 19-20
- Pages
- 1327-1332
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC8494209
- OpenAlex
- W3199777965
- Cited by
- 35
- References
- 9
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 1
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Seed Grant Program
- Hirshberg Foundation for Pancreatic Cancer Research
- NIH (R01 CA231349, P01 CA117969, R01 CA225955)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- USP21, deubiquitinase, macropinocytosis, KRAS, pancreatic ductal adenocarcinoma, MARK3, amino acid uptake, therapeutic target
- MeSH terms
- Deubiquitinating Enzymes, Animals, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Carcinoma, Pancreatic Ductal, Ubiquitin Thiolesterase, Cell Line, Tumor, Mice
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