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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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“As a crucial factor for KRAS dimerization, the intermolecular D154–R161 salt-bridges between the dimers were recently identified [66].”
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Cites
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557
Systematic identification of genomic markers of drug sensitivity in cancer cells
Garnett, M. J., Edelman, E. J., Heidorn, S. J., Greenman, C. D., Dastur, A., Lau, K. W., Greninger, P., Thompson, I. R., Luo, X., Soares, J., et al. (2012) · Nature · doi:10.1038/nature11005 · Cited by 2,456
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
Lentivirus-delivered stable gene silencing by RNAi in primary cells.
Stewart, S. A., Dykxhoorn, D. M., Palliser, D., Mizuno, H., Yu, E. Y., An, D., Sabatini, D., Chen, I. S. Y., Hahn, W., Sharp, P., et al. (2003) · RNA: A publication of the RNA Society · doi:10.1261/rna.2192803 · Cited by 1,619
BRAF mutation predicts sensitivity to MEK inhibition
Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,326
Targeting RAS–ERK signalling in cancer: promises and challenges
Samatar, A. A., & Poulikakos, P. I. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4281 · Cited by 1,163
Jonkers, J., Meuwissen, R. L. J., van der Gulden, H. M. L., Peterse, H. L., van der Valk, M., & Berns, A. J. M. (2001) · Nature Genetics · doi:10.1038/ng747 · Cited by 1,044
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations
Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., & Westover, K. D. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0203 · Cited by 786
Regulation of RAF protein kinases in ERK signalling
Lavoie, H., & Therrien, M. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3979 · Cited by 702
Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context
Guerra, C. E., Mijimolle, N., Dhawahir, A., Dubus, P. R., Barradas, M., Serrano, M., Campuzano, V., & Barbacid, M. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00191-0 · Cited by 577
Frequency-Modulated Pulses of ERK Activity Transmit Quantitative Proliferation Signals
Albeck, J. G., Mills, G. B., & Brugge, J. S. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.11.002 · Cited by 494
Puyol, M., Martín, A., Dubus, P., Mulero, F., Pizcueta, P., Khan, G., Guerra, C., Santamaría, D., & Barbacid, M. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.05.025 · Cited by 415
Self-citationThe clinical development of MEK inhibitors
Zhao, Y., & Adjei, A. A. (2014) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.83 · Cited by 410
A combinatorial strategy for treating KRAS-mutant lung cancer
Manchado, E., Weissmueller, S., Morris, J. P., Chen, C.-C., Wullenkord, R., Lujambio, A., de Stanchina, E., Poirier, J. T., Gainor, J. F., Corcoran, R. B., et al. (2016) · Nature · doi:10.1038/nature18600 · Cited by 403
Blumenschein, G. R., Smit, E. F., Planchard, D., Kim, D.-W., Cadranel, J., De Pas, T., Dunphy, F., Udud, K., Ahn, M.-J., Hanna, N. H., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv072 · Cited by 349
Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival
Drosten, M., Dhawahir, A., Sum, E. Y. M., Urosevic, J., Lechuga, C. G., Esteban, L. M., Castellano, E., Guerra, C., Santos, E., & Barbacid, M. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.7 · Cited by 347
Higher-Order Assemblies in a New Paradigm of Signal Transduction
Wu, H. (2013) · Cell · doi:10.1016/j.cell.2013.03.013 · Cited by 345
The mutational landscapes of genetic and chemical models of Kras-driven lung cancer
Westcott, P. M. K., Halliwill, K. D., To, M. D., Rashid, M., Rust, A. G., Keane, T., Delrosario, R., Jen, K., Gurley, K. E., Kemp, C. J., et al. (2014) · Nature · doi:10.1038/nature13898 · Cited by 338
Jänne, P. A., van den Heuvel, M. M., Barlesi, F., Cobo, M., Mazieres, J., Crinò, L., Orlov, S., Blackhall, F., Wolf, J., Garrido, P., et al. (2017) · JAMA · doi:10.1001/jama.2017.3438 · Cited by 335
Lito, P., Saborowski, A., Yue, J., Solomon, M., Joseph, E., Gadal, S., Saborowski, M., Kastenhuber, E., Fellmann, C., Ohara, K., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.011 · Cited by 324
Wildtype Kras2 can inhibit lung carcinogenesis in mice
Zhang, Z., Wang, Y., Vikis, H. G., Johnson, L., Liu, G., Li, J., Anderson, M. W., Sills, R. C., Hong, H. L. T., Devereux, T. R., et al. (2001) · Nature Genetics · doi:10.1038/ng721 · Cited by 295
Inhibition of RAS function through targeting an allosteric regulatory site
Spencer-Smith, R., Koide, A., Zhou, Y., Eguchi, R. R., Sha, F., Gajwani, P., Santana, D., Gupta, A., Jacobs, M., Herrero-Garcia, E., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2231 · Cited by 283
Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway
Nan, X., Tamgüney, T. M., Collisson, E. A., Lin, L.-J., Pitt, C., Galeas, J., Lewis, S., Gray, J. W., McCormick, F., & Chu, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509123112 · Cited by 273
Hunter, J. C., Gurbani, D., Ficarro, S. B., Carrasco, M. A., Lim, S. M., Choi, H. G., Xie, T., Marto, J. A., Chen, Z., Gray, N. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404639111 · Cited by 242
Young, A., Lou, D., & McCormick, F. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0231 · Cited by 211
GTP-Dependent K-Ras Dimerization
Muratcioglu, S., Chavan, T. S., Freed, B. C., Jang, H., Khavrutskii, L., Freed, R. N., Dyba, M. A., Stefanisko, K., Tarasov, S. G., Gursoy, A., et al. (2015) · Structure · doi:10.1016/j.str.2015.04.019 · Cited by 202
XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer
Kim, J., McMillan, E., Kim, H. S., Venkateswaran, N., Makkar, G., Rodriguez-Canales, J., Villalobos, P., Neggers, J. E., Mendiratta, S., Wei, S., et al. (2016) · Nature · doi:10.1038/nature19771 · Cited by 202
Inhibition of KRAS -Driven Tumorigenicity by Interruption of an Autocrine Cytokine Circuit
Zhu, Z., Aref, A. R., Cohoon, T. J., Barbie, T. U., Imamura, Y., Yang, S., Moody, S. E., Shen, R. R., Schinzel, A. C., Thai, T. C., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0646 · Cited by 193
KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer
Burgess, M. R., Hwang, E., Mroue, R., Bielski, C. M., Wandler, A. M., Huang, B. J., Firestone, A. J., Young, A., Lacap, J. A., Crocker, L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.01.020 · Cited by 183
Ambrogio, C., Goméz-López, G., Falcone, M., Vidal, A., Nadal, E., Crosetto, N., Blasco, R. B., Fernández-Marcos, P. J., Sánchez‐Céspedes, M., Ren, X., et al. (2016) · Nature Medicine · doi:10.1038/nm.4041 · Cited by 178
Self-citationPrognostic and Predictive Value in KRAS in Non–Small-Cell Lung Cancer: A Review
Wood, K., Hensing, T., Malik, R., & Salgia, R. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.0405 · Cited by 164
Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance
Castellano, E., Sheridan, C., Thin, M. Z., Nye, E., Spencer-Dene, B., Diefenbacher, M., Moore, C., Kumar, M., Murillo, M., Grönroos, E., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.012 · Cited by 161
H-Ras forms dimers on membrane surfaces via a protein–protein interface
Lin, W., Iversen, L., Tu, H., Rhodes, C., Christensen, S. M., Iwig, J. S., Hansen, S. D., Huang, W. Y. C., & Groves, J. T. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321155111 · Cited by 156
N-Ras Forms Dimers at POPC Membranes
Güldenhaupt, J., Rudack, T., Bachler, P. S., Mann, D., Triola, G., Waldmann, H., Kötting, C., & Gerwert, K. B. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.08.043 · Cited by 148
Kras regulatory elements and exon 4A determine mutation specificity in lung cancer
To, M. D., Wong, C. E., Karnezis, A. N., Rosario, R. D., Lauro, R. D., & Balmain, A. (2008) · Nature Genetics · doi:10.1038/ng.211 · Cited by 117
RAS Mutations and Oncogenesis: Not all RAS Mutations are Created Equally
Miller, M. S., & Miller, L. D. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2011.00100 · Cited by 76
Covalent Guanosine Mimetic Inhibitors of G12C KRAS
Xiong, Y., Lu, J., Hunter, J., Li, L., Scott, D., Choi, H. G., Lim, S. M., Manandhar, A., Gondi, S., Sim, T., et al. (2017) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.6b00373 · Cited by 66
He, L., Olson, D. P., Wu, X., Karpova, T., McNally, J. G., & Lipsky, P. E. (2003) · Cytometry Part A · doi:10.1002/cyto.a.10073 · Cited by 62
Chapman, P. B., Solit, D. B., & Rosen, N. X. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.10.017 · Cited by 54
Singh, A. K., Sowjanya, A. P., & Ramakrishna, G. (2005) · The FASEB Journal · doi:10.1096/fj.04-2584hyp · Cited by 47
Structural Dynamics in Ras and Related Proteins upon Nucleotide Switching
Harrison, R. A., Lu, J., Carrasco, M. A., Hunter, J., Manandhar, A., Gondi, S. R., Westover, K. D., & Engen, J. R. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.10.017 · Cited by 37
Modeling Lung Cancer Evolution and Preclinical Response by Orthotopic Mouse Allografts
Ambrogio, C., Carmona, F. J., Vidal, A., Falcone, M., Nieto, P., Romero, O. A., Puertas, S., Vizoso, M., Nadal, E., Poggio, T., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1606 · Cited by 32
Self-citationClinically Viable Gene Expression Assays with Potential for Predicting Benefit from MEK Inhibitors
Brant, R., Sharpe, A. D., Liptrot, T., Dry, J. R., Harrington, E. A., Barrett, J. C., Whalley, N., Womack, C., Smith, P. D., & Hodgson, D. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0021 · Cited by 29
Back to the Bench? MEK and ERK Inhibitors for the Treatment of KRAS Mutant Lung Adenocarcinoma
Köhler, J., Catalano, M., & Ambrogio, C. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170530093100 · Cited by 15
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- Zhou, 2015, Ras nanoclusters: Versatile lipid-based signaling platforms. Biochim. Biophys. Acta, ., 1853, 841
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RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103
Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
Salo‐Ahen, O. M. H., Alanko, I., Bhadane, R. N., Bonvin, A. M. J. J., Honorato, R. V., Hossain, S., Juffer, A. H., Kabedev, A., Lahtela-Kakkonen, M. K., Larsen, A. S., et al. (2020) · Processes · doi:10.3390/pr9010071 · Cited by 732
Therapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420
Hu, K., Li, K., Lv, J., Feng, J., Chen, J., Wu, H., Cheng, F., Jiang, W., Wang, J., Pei, H., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124049 · Cited by 409
Metadata
- 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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