KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
Open accessAbstract
The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRAS D154Q , a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.
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The intermolecular D154-R161 salt-bridges between KRAS dimers are a crucial factor for KRAS dimerization.
“As a crucial factor for KRAS dimerization, the intermolecular D154–R161 salt-bridges between the dimers were recently identified [66].”
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“[29] used both mice and RASless MEFs containing floxed WT Kras, and found that removal of WT KRAS enhanced mutant KRAS-driven signaling, proliferation, and tumorigenesis.”
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- Authors
- Ambrogio, C., Köhler, J., Zhou, Z.-W., Wang, H., Paranal, R., Li, J., Capelletti, M., Caffarra, C., Li, S., Lv, Q., Gondi, S., Hunter, J. C., Lu, J., Chiarle, R., Santamaría, D., Westover, K. D., & Jänne, P. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Tongji University (CN)
- Boston Children's Hospital (US)
- Corresponding author
- Ambrogio, Chiara
- Westover, Kenneth D.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 172
- Issue
- 4
- Pages
- 857-868.e15
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2783664968
- Cited by
- 270
- References
- 46
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 25 · 2023: 35 · 2022: 35 · 2021: 43 · 2020: 39 · 2019: 37 · 2018: 28
- FWCI
- 13.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 372 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- American Cancer Society (SU2C-AACR-DT17-15)
- Gadzooks Fund
- Cammarata Family Foundation Research Fund
- US Department of Defense (W81XWH-16-1-0106)
- Cancer Prevention and Research Institute of Texas (RP140233)
- National Natural Science Foundation of China (31571363, 31771469)
- German Cancer Aid Foundation (70111755)
- American Association for Cancer Research
- AstraZeneca
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- MEK inhibitor resistance, lung adenocarcinoma, loss of heterozygosity, KRAS wild-type, oncogenic activity
- MeSH terms
- Adenocarcinoma of Lung, Animals, Enzyme Inhibitors, Humans, Lung Neoplasms, Proto-Oncogene Proteins p21(ras), Mice, Knockout, Loss of Heterozygosity, Amino Acid Substitution, Mutation, Missense, MAP Kinase Kinase Kinases, Cell Line, Tumor, Mice, Protein Multimerization, HEK293 Cells
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