Cited by 272Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

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Ambrogio, Chiara, Köhler, Jens, Zhou, Zhi-Wei, Wang, Haiyun, Paranal, Raymond, Li, Jiaqi, Capelletti, Marzia, Caffarra, Cristina +9 more·2018·Cell

Abstract

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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Crossref · 10.1016/j.cell.2017.12.020

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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.
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
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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