The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
KRASQ61H Preferentially Signals through MAPK in a RAF Dimer-Dependent Manner in Non–Small Cell Lung Cancer
Open accessAbstract
Assembly of RAS molecules into complexes at the cell membrane is critical for RAS signaling. We previously showed that oncogenic KRAS codon 61 mutations increase its affinity for RAF, raising the possibility that KRASQ61H, the most common KRAS mutation at codon 61, upregulates RAS signaling through mechanisms at the level of RAS assemblies. We show here that KRASQ61H exhibits preferential binding to RAF relative to PI3K in cells, leading to enhanced MAPK signaling in in vitro models and human NSCLC tumors. X-ray crystallography of KRASQ61H:GTP revealed that a hyperdynamic switch 2 allows for a more stable interaction with switch 1, suggesting that enhanced RAF activity arises from a combination of absent intrinsic GTP hydrolysis activity and increased affinity for RAF. Disruption of KRASQ61H assemblies by the RAS oligomer–disrupting D154Q mutation impaired RAF dimerization and altered MAPK signaling but had little effect on PI3K signaling. However, KRASQ61H oligomers but not KRASG12D oligomers were disrupted by RAF mutations that disrupt RAF–RAF interactions. KRASQ61H cells show enhanced sensitivity to RAF and MEK inhibitors individually, whereas combined treatment elicited synergistic growth inhibition. Furthermore, KRASQ61H tumors in mice exhibited high vulnerability to MEK inhibitor, consistent with cooperativity between KRASQ61H and RAF oligomerization and dependence on MAPK signaling. These findings support the notion that KRASQ61H and functionally similar mutations may serve as predictive biomarkers for targeted therapies against the MAPK pathway. Significance: These findings show that oncogenic KRASQ61H forms a cooperative RAS–RAF ternary complex, which renders RAS-driven tumors vulnerable to MEKi and RAFi, thus establishing a framework for evaluating RAS biomarker-driven targeted therapies.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The implication of these unusual variants is that specific KRAS variants can have tissue-specific oncogenic effects and exhibit allele-specific therapeutic vulnerabilities in downstream effector pathways.”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [89]
In the citing paper
“While A146T and Q61H mutations in KRAS remain sensitive to pan-KRAS inhibitors and degraders targeting the “OFF” form of KRAS, this appears not the case for the KRAS G12R mutant which could require KRAS “ON” drugs.”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [89]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
PHENIX : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., & Bax, A. (1995) · Journal of Biomolecular NMR · doi:10.1007/bf00197809 · Cited by 15,961
Overview of the CCP 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353
MolProbity: More and better reference data for improved all‐atom structure validation
Williams, C. J., Headd, J. J., Moriarty, N. W., Prisant, M. G., Videau, L. L., Deis, L. N., Verma, V., Keedy, D. A., Hintze, B. J., Chen, V. B., et al. (2018) · Protein Science · doi:10.1002/pro.3330 · Cited by 4,599
A Comprehensive Survey of Ras Mutations in Cancer
Prior, I. A., Lewis, P. D., & Mattos, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2612 · Cited by 2,063 · cited 4×
“Most oncogenic RAS mutations occur at codons 12, 13, and 61 (1).”
BackgroundMethodInfluentialJares-Erijman, E. A., & Jovin, T. M. (2003) · Nature Biotechnology · doi:10.1038/nbt896 · Cited by 1,830
The cellular thermal shift assay for evaluating drug target interactions in cells
Jafari, R., Almqvist, H., Axelsson, H., Ignatushchenko, M., Lundbäck, T., Nordlund, P., & Molina, D. M. (2014) · Nature Protocols · doi:10.1038/nprot.2014.138 · Cited by 1,548
ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence
Cagnol, S., & Chambard, J. (2010) · The FEBS Journal · doi:10.1111/j.1742-4658.2009.07366.x · Cited by 1,290
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172
Self-citationBiochemical 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
Self-citationCombenefit: an interactive platform for the analysis and visualization of drug combinations
Veroli, G. Y. D., Fornari, C., Wang, D. Y. Q., Mollard, S., Bramhall, J. L., Richards, F. M., & Jodrell, D. I. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw230 · Cited by 762
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
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691
Self-citationNassar, N. N., Horn, G., Herrmann, C., Scherer, A., McCormick, F. P., & Wittinghofer, A. (1995) · Nature · doi:10.1038/375554a0 · Cited by 636
Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase γ
Pacold, M. E., Suire, S., Perišić, O., Lara‐González, S., Davis, C. T., Walker, E. H., Hawkins, P. T., Stephens, L., Eccleston, J. F., & Williams, R. L. (2000) · Cell · doi:10.1016/s0092-8674(00)00196-3 · Cited by 611
Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras- Driven Tumorigenesis in Mice
Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B., Nye, E. L., Stamp, G., Alitalo, K. K., & Downward, J. (2007) · Cell · doi:10.1016/j.cell.2007.03.051 · Cited by 603
Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Yao, Z., Yaeger, R., Rodrik-Outmezguine, V. S., Tao, A., Torres, N. M., Chang, M. T., Drosten, M., Zhao, H., Cecchi, F., Hembrough, T., et al. (2017) · Nature · doi:10.1038/nature23291 · Cited by 562
SynergyFinder: a web application for analyzing drug combination dose–response matrix data
Ianevski, A., He, L., Aittokallio, T. A., & Tang, J. P. (2017) · Bioinformatics · doi:10.1093/bioinformatics/btx162 · Cited by 535
Ihle, N. T., Byers, L. A., Kim, E. S., Saintigny, P., Lee, J. J., Blumenschein, G. R., Tsao, A., Liu, S., Larsen, J. E., Wang, J., et al. (2012) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djr523 · Cited by 532
A dimerization-dependent mechanism drives RAF catalytic activation
Rajakulendran, T., Sahmi, M., Lefrançois, M., Sicheri, F., & Therrien, M. (2009) · Nature · doi:10.1038/nature08314 · Cited by 505
Plasma membrane nanoswitches generate high-fidelity Ras signal transduction
Tian, T., Harding, A. S., Inder, K. L., Plowman, S. J., Parton, R. G., & Hancock, J. F. (2007) · Nature Cell Biology · doi:10.1038/ncb1615 · Cited by 407
KRAS Alleles: The Devil Is in the Detail
Haigis, K. M. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.08.006 · Cited by 373
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
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
RAS and RHO Families of GTPases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms
Fritsch, R., de Krijger, I., Fritsch, K., George, R., Reason, B., Kumar, M. S., Diefenbacher, M. E., Stamp, G., & Downward, J. (2013) · Cell · doi:10.1016/j.cell.2013.04.031 · Cited by 323
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
KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
Ambrogio, C., Köhler, J., Zhou, Z.-W., Wang, H., Paranal, R., Li, J., Capelletti, M., Caffarra, C., Li, S., Lv, Q., et al. (2018) · Cell · doi:10.1016/j.cell.2017.12.020 · Cited by 270
Self-citationEffects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling
Freeman, A. K., Ritt, D. A., & Morrison, D. K. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.018 · 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
Tissue-Specific Oncogenic Activity of KRASA146T
Poulin, E. J., Bera, A. K., Lu, J., Lin, Y.-J., Strasser, S. D., Paulo, J. A., Huang, T. Q., Morales, C., Yan, W., Cook, J., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1220 · Cited by 197
Self-citationA single amino acid change in Raf-1 inhibits Ras binding and alters Raf-1 function.
Fabian, J. R., Vojtek, A. B., Cooper, J. A., & Morrison, D. K. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.13.5982 · Cited by 193
Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization
Lavoie, H., Thevakumaran, N., Gavory, G., Li, J. J., Padeganeh, A., Guiral, S., Duchaine, J., Mao, D. Y. L., Bouvier, M., Sicheri, F., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1257 · Cited by 181
Self-citationSpoerner, M., Hozsa, C., Poetzl, J. A., Reiss, K., Ganser, P., Geyer, M., & Kalbitzer, H. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.145235 · Cited by 148
Role of Bim in the survival pathway induced by Raf in epithelial cells
Marani, M., Hancock, D. C., Lopes, R., Tenev, T., Downward, J., & Lemoine, N. R. (2003) · Oncogene · doi:10.1038/sj.onc.1207364 · Cited by 114
Terrell, E. M., Durrant, D., Ritt, D. A., Sealover, N. E., Sheffels, E., Spencer-Smith, R., Esposito, D., Zhou, Y., Hancock, J. F., Kortum, R. L., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.004 · Cited by 110
Electrostatic Interactions Positively Regulate K-Ras Nanocluster Formation and Function
Plowman, S. J., Ariotti, N., Goodall, A., Parton, R. G., & Hancock, J. F. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00050-08 · Cited by 108
Xu, C., Jere, D., Jin, H., Chang, S.-H., Chung, Y.-S., Shin, J., Kim, J., Park, S. J., Lee, Y.-H., Chae, C., et al. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200707-1022oc · Cited by 102
Self-citationRAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition
Jin, T., Lavoie, H., Sahmi, M., David, M., Hilt, C., Hammell, A., & Therrien, M. (2017) · Nature Communications · doi:10.1038/s41467-017-01274-0 · Cited by 101
Spectrum of LKB1, EGFR, and KRAS Mutations in Chinese Lung Adenocarcinomas
Gao, B., Sun, Y., Zhang, J., Ren, Y., Fang, R., Han, X., Shen, L., Liu, X., Pao, W. J., Chen, H., et al. (2010) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181e05016 · Cited by 98
Prakash, P., Sayyed–Ahmad, A., Cho, K.-J., Dolino, D. M., Chen, W., Li, H., Grant, B. J., Hancock, J. F., & Gorfe, A. A. (2017) · Scientific Reports · doi:10.1038/srep40109 · Cited by 93
Lee, K., Fang, Z., Enomoto, M., Gasmi-Seabrook, G. M. C., Zheng, L., Koide, S., Ikura, M., & Marshall, C. B. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202001758 · Cited by 78
KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation
Lu, J., Bera, A. K., Gondi, S. R., & Westover, K. D. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00974 · Cited by 51
Self-citationZheng, D., Chen, H., Wang, R., Zhang, Y., Pan, Y., Cheng, X., Cheng, C., Zheng, S., Li, H., Gong, R., et al. (2016) · OncoTargets and Therapy · doi:10.2147/ott.s96834 · Cited by 46
Shao, W., Mishina, Y. M., Feng, Y., Caponigro, G., Cooke, V. G., Rivera, S., Wang, Y., Shen, F., Korn, J. M., Griner, L. A. M., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2033 · Cited by 44
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
Self-citationQuantitative Measurement of Intrinsic GTP Hydrolysis for Carcinogenic Glutamine 61 Mutants in H-Ras
Novelli, E. T., First, J. T., & Webb, L. J. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00878 · Cited by 33
Structural basis of the atypical activation mechanism of KRASV14I
Bera, A. K., Lu, J., Wales, T. E., Gondi, S. R., Gurbani, D., Nelson, A., Engen, J. R., & Westover, K. D. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009131 · Cited by 31
Self-citationProgress on Covalent Inhibition of KRASG12C
Westover, K. D., Janne, P. A., & Gray, N. S. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0092 · Cited by 21
Self-citation
Cited by
Sorted by citations
Hofmann, M. H., Gmachl, M., Ramharter, J., Savarese, F., Gerlach, D., Marszalek, J. R., Sanderson, M. P., Kessler, D., Trapani, F., Arnhof, H., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0142 · Cited by 444
Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M., & Kraut, N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1331 · Cited by 336
Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers
Kobayashi, Y., Chhoeu, C., Li, J., Price, K. S., Kiedrowski, L. A., Hutchins, J. L., Hardin, A. I., Wei, Z., Hong, F., Bahcall, M., et al. (2022) · Nature · doi:10.1038/s41586-022-04451-4 · Cited by 56
Self-citationGebregiworgis, T., Kano, Y., St-Germain, J., Radulovich, N., Udaskin, M. L., Mentes, A., Huang, R., Poon, B. P. K., He, W., Valencia-Sama, I., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26526-y · Cited by 49
Ricciuti, B., Son, J., Okoro, J. J., Mira, A., Patrucco, E., Eum, Y., Wang, X., Paranal, R., Wang, H., Lin, M., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2719 · Cited by 42
Self-citation
Metadata
- Authors
- Zhou, Z.-W., Ambrogio, C., Bera, A. K., Li, Q., Li, X.-X., Li, L., Son, J., Gondi, S., Li, J., Campbell, E., Jin, H., Okoro, J. J., Xu, C.-X., Janne, P. A., & Westover, K. D.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Army Medical University (CN)
- Brigham Young University (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2020-09-01
- Volume
- 80
- Issue
- 17
- Pages
- 3719-3731
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W3038485915
- Cited by
- 60
- References
- 51
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 12 · 2020: 1
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Funders
- V Foundation (DOD W81XWH-16-1-0106, CPRIT RP170373)
- Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15)
- 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
- Ras-Raf interaction, RAF dimerization, MAPK signaling, PI3K signaling, MEK inhibitors, RAF inhibitors, combination therapy synergy, predictive biomarkers, non-small cell lung cancer, targeted therapy
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras), MAP Kinase Signaling System, raf Kinases, Mice, HEK293 Cells, Heterografts
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
