KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

Rabara, Dana; Tran, Timothy H.; Dharmaiah, Srisathiyanarayanan; Stephens, Robert M.; McCormick, Frank; Simanshu, Dhirendra K.; Holderfield, Matthew

doi:10.1073/pnas.1908353116

Cited by 128Protein Kinase Regulation and GTPase SignalingNeurofibromatosis and Schwannoma CasesProtein Tyrosine Phosphatases

KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

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Rabara, Dana, Tran, Timothy H., Dharmaiah, Srisathiyanarayanan, Stephens, Robert M., McCormick, Frank, Simanshu, Dhirendra K., Holderfield, Matthew·2019·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1908353116PMC PMC6825300

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Abstract

KRAS mutations occur in ∼35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway. KRAS mutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and render KRAS -mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here that KRAS G13-mutated cancer cells are frequently comutated with NF1 GAP but NF1 is rarely mutated in cancers with KRAS codon 12 or 61 mutations. Neurofibromin protein (encoded by the NF1 gene) hydrolyzes GTP directly in complex with KRAS G13D, and KRAS G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Structures of the wild type and G13D mutant of KRAS in complex with neurofibromin (RasGAP domain) provide the structural basis for neurofibromin-mediated GTP hydrolysis. These results reveal that KRAS G13D is responsive to neurofibromin-stimulated hydrolysis and suggest that a subset of KRAS G13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.

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Differential interaction kinetics between KRAS G13D and the Ras GAP NF-1 explain the sensitivity of KRAS G13D COAD tumors to anti-EGFR therapies.
“differential interaction kinetics between KRAS G13D and the Ras GAP NF-1 explain this effect22–24”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [23]
Codon 13 mutations can exhibit intermediate sensitivity to NF1-mediated hydrolysis while codons 12 and 61 mutations are insensitive to NF1-mediated hydrolysis.
“Codon 13 mutations can exhibit intermediate sensitivity to NF1-mediated hydrolysis while codons 12 and 61 mutations are insensitive to NF1-mediated hydrolysis [45].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [45]

Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
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 · see citing works
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455 · see citing works
Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2004088 · Cited by 15,160 · see citing works
PHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334 · see citing works
Mutational heterogeneity in cancer and the search for new cancer-associated genes
Lawrence, M. S., Stojanov, P., Polak, P., Kryukov, G. V., Cibulskis, K., Sivachenko, A., Carter, S. L., Stewart, C., Mermel, C. H., Roberts, S. A., et al. (2013) · Nature · doi:10.1038/nature12213 · Cited by 5,461 · see citing works
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 · see citing works
Self-citation
The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997) · Science · doi:10.1126/science.277.5324.333 · Cited by 1,543 · see citing works
Collaboration gets the most out of software
Morin, A., Eisenbraun, B., Key, J., Sanschagrin, P. C., Timony, M. A., Ottaviano, M., & Piotr Sliz, A. (2013) · eLife · doi:10.7554/elife.01456 · Cited by 1,034 · see citing works
RAS isoforms and mutations in cancer at a glance
Hobbs, G. A., Der, C. J., & Rossman, K. L. (2016) · Journal of Cell Science · doi:10.1242/jcs.182873 · Cited by 973 · see citing works
Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?
Vigil, D., Cherfils, J., Rossman, K. L., & Der, C. J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2960 · Cited by 816 · see citing works
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 · see citing works
Association of KRAS p.G13D Mutation with Outcome in Patients with Chemotherapy-Refractory Metastatic Colorectal Cancer Treated with Cetuximab
De Roock, W., Jonker, D. J., Di Nicolantonio, F., Sartore-Bianchi, A., Tu, D., Siena, S., Lamba, S., Arena, S., Frattini, M., Piessevaux, H., et al. (2010) · JAMA · doi:10.1001/jama.2010.1535 · Cited by 748 · see citing works
Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis
Grünert, S., Jechlinger, M., & Beug, H. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1175 · Cited by 677 · see citing works
Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome
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 · see citing works
Structure at 1.65 Å of RhoA and its GTPase-activating protein in complex with a transition-state analogue
Rittinger, K., Walker, P. A., Eccleston, J. F., Smerdon, S. J., & Gamblin, S. J. (1997) · Nature · doi:10.1038/39651 · Cited by 490 · see citing works
Implications for KRAS status and EGFR-targeted therapies in metastatic CRC
Normanno, N., Tejpar, S., Morgillo, F., De Luca, A., Van Cutsem, E., & Ciardiello, F. (2009) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2009.111 · Cited by 436 · see citing works
GTPase-activating proteins: Helping hands to complement an active site
Scheffzek, K., Ahmadian, M. R., & Wittinghofer, A. (1998) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01224-9 · Cited by 410 · see citing works
Association of KRAS G13D Tumor Mutations With Outcome in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy With or Without Cetuximab
Tejpar, S., Celik, I., Schlichting, M., Sartorius, U., Bokemeyer, C., & Van Cutsem, E. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.2592 · Cited by 353 · see citing works
Malignancy in Neurofibromatosis Type 1
Korf, B. R. (2000) · The Oncologist · doi:10.1634/theoncologist.5-6-477 · Cited by 328 · see citing works
Therapeutic Strategies for Targeting Ras Proteins
Gysin, S., Salt, M. B., Young, A. E., & McCormick, F. (2011) · Genes & Cancer · doi:10.1177/1947601911412376 · Cited by 321 · see citing works
Self-citation
Mutational and Kinetic Analyses of the GTPase-Activating Protein (GAP)-p21 Interaction: The C-Terminal Domain of GAP Is Not Sufficient for Full Activity
Gideon, P., John, J., Frech, M., Lautwein, A., Clark, R., Scheffler, J. E., & Wittinghofer, A. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.5.2050 · Cited by 287 · see citing works
Mutant KRAS Codon 12 and 13 Alleles in Patients With Metastatic Colorectal Cancer: Assessment As Prognostic and Predictive Biomarkers of Response to Panitumumab
Peeters, M., Douillard, J.-Y., Van Cutsem, E., Siena, S., Zhang, K., Williams, R., & Wiezorek, J. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.1492 · Cited by 232 · see citing works
The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B
Lu, S., Jang, H., Nussinov, R., & Zhang, J. (2016) · Scientific Reports · doi:10.1038/srep21949 · Cited by 219 · see citing works
Ras Stabilization Through Aberrant Activation of Wnt/β-Catenin Signaling Promotes Intestinal Tumorigenesis
Jeong, W.-J., Yoon, J., Park, J., Lee, S.-H., Lee, S., Kaduwal, S., Kim, H., Yoon, J., & Choi, K. (2012) · Science Signaling · doi:10.1126/scisignal.2002242 · Cited by 189 · see citing works
Structural analysis of the GAP‐related domain from neurofibromin and its implications
Scheffzek, K., Ahmadian, M. R., Wiesmüller, L., Kabsch, W., Stege, P., Schmitz, F., & Wittinghofer, A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.15.4313 · Cited by 178 · see citing works
Individual Rate Constants for the Interaction of Ras Proteins with GTPase-Activating Proteins Determined by Fluorescence Spectroscopy
Ahmadian, M. R., Hoffmann, U., Goody, R. S., & Wittinghofer, A. (1997) · Biochemistry · doi:10.1021/bi962556y · Cited by 141 · see citing works
The GAP arginine finger movement into the catalytic site of Ras increases the activation entropy
Kötting, C., Kallenbach‐Thieltges, A., Suveyzdis, Y., Wittinghofer, A., & Gerwert, K. B. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712095105 · Cited by 126 · see citing works
Regulation of the inducible nuclear dual-specificity phosphatase DUSP5 by ERK MAPK
Kucharska, A., Rushworth, L. K., Staples, C. J., MORRICE, N. A., & Keyse, S. M. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.07.015 · Cited by 114 · see citing works
Kinetics of interaction between normal and proline 12 Ras and the GTPase-activating proteins, p120-GAP and neurofibromin. The significance of the intrinsic GTPase rate in determining the transforming ability of ras.
Eccleston, J. F., Moore, K. J. M., Morgan, L. K., Skinner, R. H., & Lowe, P. N. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74211-2 · Cited by 104 · see citing works
Structural Differences in the Minimal Catalytic Domains of the GTPase-activating Proteins p120GAP and Neurofibromin
Ahmadian, M. R., Wiesmüller, L., Lautwein, A., Bischoff, F. R., & Wittinghofer, A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.27.16409 · Cited by 80 · see citing works
Interaction of GTPase activating proteins (GAPs) with p21ras measured by a novel fluorescence anisotropy method. Essential role of Arg-903 of GAP in activation of GTP hydrolysis on p21ras
Brownbridge, G. G., Lowe, P. N., Moore, K. J. M., Skinner, R. H., & Webb, M. R. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82072-5 · Cited by 79 · see citing works
Identification of mutant K-Ras-dependent phenotypes using a panel of isogenic cell lines
Vartanian, S., Bentley, C., Brauer, M. J., Li, L., Shirasawa, S., Sasazuki, T., Kim, J.-S., Haverty, P., Stawiski, E., Modrusan, Z., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.394130 · Cited by 65 · see citing works
Biochemical Characterization of a Novel KRAS Insertion Mutation from a Human Leukemia
Bollag, G. E., Adler, F., elMasry, N., McCabe, P. C., Conner, E. R., Thompson, P., McCormick, F. P., & Shannon, K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32491 · Cited by 63 · see citing works
Self-citation
Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study
Segelov, E., Thavaneswaran, S., Waring, P. M., Desai, J., Robledo, K. P., Gebski, V., Élez, E., Nott, L. M., Karapetis, C. S., Lunke, S., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.65.6843 · Cited by 59 · see citing works
Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGAP interaction
Gremer, L., Gilsbach, B. K., Ahmadian, M. R., & Wittinghofer, A. (2008) · Biological Chemistry · doi:10.1515/bc.2008.132 · Cited by 54 · see citing works
Mutational and Kinetic Analyses of the GTPase-Activating Protein (GAP)-p21 Interaction: The C-Terminal Domain of GAP Is Not Sufficient for Full Activity
Gideon, P., John, J., Frech, M., et al. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.5.2050-2056.1992 · Cited by 49 · see citing works
Reciprocal regulation of extracellular signal regulated kinase 1/2 and mitogen activated protein kinase phosphatase-3
Zeliadt, N. A., Mauro, L. J., & Wattenberg, E. V. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2008.08.007 · Cited by 25 · see citing works
Are all KRAS mutations created equal?
Stinchcombe, T. E., & Der, C. J. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70200-5 · Cited by 12 · see citing works

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Huang, L., Guo, Z., Wang, F., & Fu, L. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00780-4 · Cited by 1,127 · see citing works
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 · see citing works
Self-citation
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 693 · see citing works
Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy
Degirmenci, U., Wang, M., & Hu, J. (2020) · Cells · doi:10.3390/cells9010198 · Cited by 541 · see citing works
Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy
Holderfield, M., Lee, B. J., Jiang, J., Tomlinson, A., Seamon, K. J., Mira, A., Patrucco, E., Goodhart, G., Dilly, J., Gindin, Y., et al. (2024) · Nature · doi:10.1038/s41586-024-07205-6 · Cited by 369 · see citing works
“are frequently co-mutated with NF1 or receptor tyrosine kinase (RTK) genes, which may affect RAS dependency and, by extension, RMC-7977 sensitivity 24 .”
BackgroundSelf-citation
The current understanding of KRAS protein structure and dynamics
Pantsar, T. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.12.004 · Cited by 288 · see citing works
Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients
Kim, D., Xue, J. Y., & Lito, P. (2020) · Cell · doi:10.1016/j.cell.2020.09.044 · Cited by 239 · see citing works
The origins and genetic interactions of KRAS mutations are allele- and tissue-specific
Cook, J. H., Melloni, G. E. M., Gulhan, D. C., Park, P. J., & Haigis, K. M. (2021) · Nature Communications · doi:10.1038/s41467-021-22125-z · Cited by 208 · see citing works
Neurofibromin Structure, Functions and Regulation
Bergoug, M., Doudeau, M., Godin, F., Mosrin-Huaman, C., Vallée, B., & Bénédetti, H. (2020) · Cells · doi:10.3390/cells9112365 · Cited by 182 · see citing works
“More recently, the 3D structure of a complex between K-Ras (GMPPNP-bound) and a fragment of the neurofibromin-GRD (GAP255: residues 1209 to 1463), corresponding to the minimum catalytic region (the C- and N-terminal regions forming the extra domain were excluded), was resolved [47] (Figure 5), confirming the insights…”
Background
Drugging KRAS: Current perspectives and state-of-art review
Parikh, K., Banna, G., Liu, S. V., Friedlaender, A., Desai, A., Subbiah, V., & Addeo, A. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01375-4 · Cited by 164 · see citing works
An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants
Zafra, M. P., Parsons, M. J., Kim, J., Alonso-Curbelo, D., Goswami, S., Schatoff, E. M., Han, T., Katti, A., Fernandez, M. T. C., Wilkinson, J. E., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0442 · Cited by 139 · see citing works
“is consistent with retrospective clinical data in colorectal cancer (6,7), and two recent publications using cancer cell lines (36,37).”
BackgroundResult
Classification of KRAS -Activating Mutations and the Implications for Therapeutic Intervention
Johnson, C. W., Burkhart, D. L., & Haigis, K. M. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0035 · Cited by 130 · see citing works
The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS
Li, C., Vides, A., Kim, D., Xue, J. Y., Zhao, Y., & Lito, P. (2021) · Science · doi:10.1126/science.abf1730 · Cited by 103 · see citing works
Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance
Reita, D., Pabst, L., Pencreach, E., Guérin, É., Dano, L., Rimelen, V., Voegeli, A., Vallat, L. D., Mascaux, C., & Beau‐Faller, M. (2022) · Cancers · doi:10.3390/cancers14051321 · Cited by 101 · see citing works
“As the covalent inhibitors required KRAS-G12C to be in the inactive GDP-bound state, resistant mutations could arise in KRAS G12C that disable the GTPase activity or that promote the guanine exchange of GDP to GTP. Proposed resistance mechanisms to covalent KRAS-G12C covalent inhibitors have been identified in vitro t…”
BackgroundInfluential
Dynamic regulation of RAS and RAS signaling
Kölch, W., Berta, D., & Rosta, E. (2023) · Biochemical Journal · doi:10.1042/bcj20220234 · Cited by 91 · see citing works
A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers
Cheng, R., Li, F., Zhang, M., Xia, X., Wu, J., Gao, X., Zhou, H., Zhang, Z., Huang, N., Yang, X., et al. (2022) · Cell Research · doi:10.1038/s41422-022-00726-7 · Cited by 87 · see citing works
Conformations of KRAS4B Affected by Its Partner Binding and G12C Mutation: Insights from GaMD Trajectory-Image Transformation-Based Deep Learning
Chen, J., Wang, J., Yang, W., Zhao, L., & Hu, G. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c01174 · Cited by 82 · see citing works
A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
Simanshu, D. K., & Morrison, D. K. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1494 · Cited by 74 · see citing works
“Interestingly, structures of KRASG13D in complex with the RASGAP domain of NF1 have indicated that in contrast to substitutions at G12 and Q61, the G13D mutation allows the arginine finger of NF1 to enter the catalytic pocket for NF1-mediated GTP hydrolysis (29).”
BackgroundResultInfluentialSelf-citation
Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR
Yan, W., Markegard, E., Dharmaiah, S., Urisman, A., Drew, M. R., Esposito, D., Scheffzek, K., Nissley, D. V., McCormick, F. P., & Simanshu, D. K. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107909 · Cited by 68 · see citing works
“This explains why the KRAS-Q61R mutant binds to NF1 with a much lower affinity than KRASQ61L (Rabara et al., 2019).”
BackgroundInfluentialSelf-citation
Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development—a narrative review
Santarpia, M., Ciappina, G., Spagnolo, C. C., Squeri, A., Passalacqua, M. I., Aguilar, A., Gonzalez-Cao, M., Giovannetti, E., Silvestris, N., & Rosell, R. (2023) · Translational Lung Cancer Research · doi:10.21037/tlcr-22-639 · Cited by 65 · see citing works
“Moreover, KRAS mutations at codons 12 and 61 have been shown to be insensitive to NF1 GAP-mediated hydrolysis (48).”
Background
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“G13D mutations also increase sensitivity to NF1 [31].”
Background
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Naschberger, A., Baradaran, R., Rupp, B., & Carroni, M. (2021) · Nature · doi:10.1038/s41586-021-04024-x · Cited by 62 · see citing works
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Xiong, D., Qiu, Y., Zhao, J., Zhou, Y., Lee, D., Gupta, S., Torres, M., Lü, W., Liang, S., Kang, J. J., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02428-4 · Cited by 49 · see citing works
“KRAS has been reported to co-mutate with NF1 in response to GTP hydrolysis 55 .”
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Self-citation
Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers
Scharpf, R. B., Balan, A., Ricciuti, B., Fiksel, J., Cherry, C., Wang, C., Lenoue-Newton, M. L., Rizvi, H. A., White, J. R., Baras, A. S., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1731 · Cited by 45 · see citing works
“Interest-ingly, NF1 mutations were less frequent in KRAS codon 12 – mutant NSCLC compared with KRAS codon 13 – mutant NSCLC, suggesting codon-speci ﬁ c RAS oncogenicity (40), which may result in positive selection of NF1 mutations in non-codon 12 KRAS -mutant NSCLC (9, 41).”
KRAS Mutations in Cancer: Understanding Signaling Pathways to Immune Regulation and the Potential of Immunotherapy
Uniyal, P., Kashyap, V. K., Behl, T., Parashar, D., & Rawat, R. (2025) · Cancers · doi:10.3390/cancers17050785 · Cited by 45 · see citing works
“Furthermore, KRAS (G13) is slightly delicate for neurofibromin 1, while KRAS (G12) and (Q61) are resistant/hypersensitive to the hydrolysis induced by neurofibromin 1, a kind of GAP [93].”
Not all RAS mutations are equal: A detailed review of the functional diversity of RAS hot spot mutations
Burge, R. A., & Hobbs, G. A. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2021.07.004 · Cited by 44 · see citing works
Small molecular inhibitors for KRAS-mutant cancers
Wu, X., Song, W., Cheng, C., Liu, Z., Li, X., Cui, Y., Gao, Y., & Ding, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1223433 · Cited by 41 · see citing works
“Frontiers in Immunology 03 However, KRAS-G13D displays heightened intrinsic exchange activity compared to the wild-type RAS protein (37, 38).”
Background
Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice
Tolani, B., Celli, A., Yao, Y., Tan, Y. Z., Fetter, R. D., Liem, C. R., de Smith, A. J., Vasanthakumar, T., Bisignano, P., Cotton, A. D., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01386-z · Cited by 40 · see citing works
“Available evidence, such as differences in signaling in cells expressing different Ras mutants 36,51–53 , increasingly suggests that there may not be a single anti-Ras therapeutic approach for all Ras-mutant cancers; instead, mutation-specific therapeutic strategies must be deployed for different…”
Comparative analysis of KRAS4a and KRAS4b splice variants reveals distinctive structural and functional properties
Whitley, M. J., Tran, T. H., Rigby, M., Yi, M., Dharmaiah, S., Waybright, T. J., Ramakrishnan, N., Perkins, S. C., Taylor, T. E., Messing, S. A. J., et al. (2024) · Science Advances · doi:10.1126/sciadv.adj4137 · Cited by 39 · see citing works
Self-citation
Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes
Chen, J., Zeng, Q., Wang, W., Hu, Q., & Bao, H. (2022) · RSC Advances · doi:10.1039/d1ra07936k · Cited by 39 · see citing works
Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS
Roskoski, R. J. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105806 · Cited by 38 · see citing works
Targeting KRAS in PDAC: A New Way to Cure It?
He, Q., Liu, Z., & Wang, J. (2022) · Cancers · doi:10.3390/cancers14204982 · Cited by 36 · see citing works
“For example, KRASG13 mutation is more sensitive to NF1-GAP-mediated hydrolytic activity, while KRASG12 and KRASQ61 mutations are insensitive to it [62].”
Background
Molecular Mechanism of Phosphorylation-Mediated Impacts on the Conformation Dynamics of GTP-Bound KRAS Probed by GaMD Trajectory-Based Deep Learning
Chen, J., Wang, J., Yang, W., Zhao, L., Zhao, J., & Hu, G. (2024) · Molecules · doi:10.3390/molecules29102317 · Cited by 34 · see citing works
Delineating the RAS Conformational Landscape
Parker, M. I., Meyer, J. E., Golemis, E. A., & Dunbrack (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0804 · Cited by 30 · see citing works
“State” (9) by others], the R-finger can enter the active site to potentially interact with GTP.”
Background
Mechanistic Insights into the Long-range Allosteric Regulation of KRAS Via Neurofibromatosis Type 1 (NF1) Scaffold Upon SPRED1 Loading
Li, M.-Y., Wang, Y., Fan, J., Zhuang, H., Liu, Y., Ji, D., & Lu, S. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167730 · Cited by 31 · see citing works
Making NSCLC Crystal Clear: How Kinase Structures Revolutionized Lung Cancer Treatment
Vilachã, J. F., Mitchel, S. C., Akele, M. Z., Evans, S., & Groves, M. R. (2020) · Crystals · doi:10.3390/cryst10090725 · Cited by 29 · see citing works
KRAS-targeted therapies in colorectal cancer: a systematic analysis of mutations, inhibitors, and clinical trials
Navarro-Jiménez, M., González, B., Mulet-Margalef, N., Hierro, C., & Alonso, S. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01166-3 · Cited by 33 · see citing works
Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach
McFall, T. B., & Stites, E. C. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110096 · Cited by 29 · see citing works
“Co-occurring mutations can also promote resistance; in earlier work, both we and a separate group identified NF1 loss-of-function/loss-of-expression mutations as a mechanism of resistance for KRAS G13D mutant cancers (McFall et al., 2019; Rabara et al., 2019).”
Influential
Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers
Adachi, Y., Kimura, R., Hirade, K., & Ebi, H. (2021) · Cancers · doi:10.3390/cancers13205081 · Cited by 28 · see citing works
“Since NF1 is frequently co-mutated in KRAS G13-mutated colorectal cancer, these tumor cells can respond to EGFR inhibitors in an NF1-dependent manner [14].”
Background
Discernment between candidate mechanisms for KRAS G13D colorectal cancer sensitivity to EGFR inhibitors
McFall, T. B., Schomburg, N. K., Rossman, K. L., & Stites, E. C. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00645-3 · Cited by 25 · see citing works
“Rabara et al posit that KRAS G13D retains sensitivity to NF1, and that inhibition of EGFR can thereby result in a reduction of active, GTP-bound, KRAS G13D through NF1 activity on KRAS G13D [18].”
BackgroundInfluential
RAS‐targeted cancer therapy: Advances in drugging specific mutations
Liu, C., Ye, D., Yang, H., Chen, X., Su, Z., Li, X., Ding, M., & Liu, Y. (2023) · MedComm · doi:10.1002/mco2.285 · Cited by 24 · see citing works
Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes
Avolio, M., & Trusolino, L. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1531 · Cited by 24 · see citing works
Targeting RAS in neuroblastoma: Is it possible?
Lin, L., Miao, L., Lin, H., Cheng, J., Li, M., Zhuo, Z., & He, J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108054 · Cited by 24 · see citing works
Lung cancer molecular mutations and abnormal glycosylation as biomarkers for early diagnosis
Yang, S., Xia, J., Yang, Z., Xu, M., & Li, S. (2021) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2021.100311 · Cited by 23 · see citing works
Normal Mode Analysis of KRas4B Reveals Partner Specific Dynamics
Eren, M., Tunçbağ, N., Jang, H., Nussinov, R., Gürsoy, A., & Keskin, Ö. (2021) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.1c00891 · Cited by 22 · see citing works
Biophysical and structural analysis of KRAS switch-II pocket inhibitors reveals allele-specific binding constraints
Alexander, P., Chan, A. H., Rabara, D., Swain, M., Larsen, E. K., Dyba, M. D., Chertov, O., Ashraf, M., Champagne, A., Lin, K. Y., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110331 · Cited by 21 · see citing works
Self-citation
NF1, Neurofibromin and Gene Therapy: Prospects of Next-Generation Therapy
Cui, X.-W., Ren, J.-Y., Gu, Y., Li, Q., & Wang, Z. (2020) · Current Gene Therapy · doi:10.2174/1566523220666200806111451 · Cited by 22 · see citing works
A brief history of RAS and the RAS Initiative
McCormick, F. P. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2021.07.003 · Cited by 19 · see citing works
Self-citation
Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives
Tisi, R., Gaponenko, V., Vanoni, M., & Sacco, E. (2020) · Biomolecules · doi:10.3390/biom10111535 · Cited by 18 · see citing works
Targeting protein conformations with small molecules to control protein complexes
Zacharioudakis, E., & Gavathiotis, E. (2022) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2022.07.002 · Cited by 18 · see citing works
Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer
Bellazzo, A., & Collavin, L. (2020) · Cancers · doi:10.3390/cancers12103066 · Cited by 16 · see citing works
“Interestingly, some mutant K-Ras proteins remain susceptible to GAP-mediated GTP hydrolysis, so RasGAPs can buffer the oncogenic potential of RAS mutation [51,107].”
Background
Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations
Zeng, J., Chen, J., Xia, F., Cui, Q., Deng, X., & Xu, X. (2022) · Physical Chemistry Chemical Physics · doi:10.1039/d2cp00274d · Cited by 16 · see citing works
Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis
Roux, Ö. L., Pershing, N. L., Kaltenbrun, E., Newman, N. J., Everitt, J. I., Baldelli, E., Pierobon, M., Petricoin, E. F., & Counter, C. M. (2022) · eLife · doi:10.7554/elife.75715 · Cited by 15 · see citing works
Reduced dynamic complexity allows structure elucidation of an excited state of KRASG13D
Chao, F.-A., Chan, A. H., Dharmaiah, S., Schwieters, C. D., Tran, T. H., Taylor, T. E., Ramakrishnan, N., Esposito, D., Nissley, D. V., McCormick, F. P., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-04960-6 · Cited by 14 · see citing works
“coli gene-optimized fragments containing an upstream tobacco etch virus (TEV) protease site (ENLYFQ/G) followed by the coding sequence of human KRAS4b(1-169) or human RAF1(52-131).”
BackgroundInfluentialSelf-citation
Targeting KRAS Oncogene for Patients With Colorectal Cancer: A New Step Toward Precision Medicine
Şahin, İ. H., Saridogan, T., Ayasun, R., Syed, M. P., Gorantla, V. C., Malhotra, M. K., Thomas, R. A., Rhee, J. C., Zhang, J. Y., Hsu, D. J., et al. (2024) · JCO Oncology Practice · doi:10.1200/op.23.00787 · Cited by 13 · see citing works
Paneth-like cells produced from OLFM4+ stem cells support OLFM4+ stem cell growth in advanced colorectal cancer
Sakahara, M., Okamoto, T., Srivastava, U., Natsume, Y., Yamanaka, H., Suzuki, Y., Obama, K., Nagayama, S., & Yao, R. (2024) · Communications Biology · doi:10.1038/s42003-023-05504-8 · Cited by 13 · see citing works
RAS internal tandem duplication disrupts GTPase-activating protein (GAP) binding to activate oncogenic signaling
Nelson, A., Turbyville, T. J., Dharmaiah, S., Rigby, M., Yang, R., Wang, T.-Y., Columbus, J., Stephens, R. M., Taylor, T. E., Sciacca, D., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011080 · Cited by 13 · see citing works
“ITC experiments showed that WT NRAS and KRAS bound to NF1 (GRD, GAP-related domain) with high affinity (Kd = 1 mM) as reported previously (19), whereas ITD mutants of NRAS and KRAS showed complete loss of binding to NF1, suggesting that the ITD resulted in fully impaired GAP-medi-”
BackgroundResultSelf-citation
Allosteric modulation of NF1 GAP : Differential distributions of catalytically competent populations in loss‐of‐function and gain‐of‐function mutants
Xu, L., Jang, H., & Nussinov, R. (2025) · Protein Science · doi:10.1002/pro.70042 · Cited by 11 · see citing works
“The crystal structure of wild-type K-Ras4B (GMPPNP-bound) in complex with the GRD of NF1 (PDB ID: 6OB2) (Rabara et al. 2019) was used to construct the initial structural model.”
Influential
Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activityPreprint
Kwon, J. J., Dilly, J., Liu, S., Kim, E., Bian, Y., Dharmaiah, S., Tran, T. H., Kapner, K. S., Ly, S. H., Yang, X., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.22.618529 · Cited by 11 · see citing works
Self-citation
Beyond structural bioinformatics for genomics with dynamics characterization of an expanded KRAS mutational landscape
Ratnasinghe, B. D., Haque, N., Wagenknecht, J. B., Jensen, D. R., Esparza, G. K. V., Leverence, E. N., de Assuncao, T. M., Mathison, A., Lomberk, G. A., Smith, B. C., et al. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.10.003 · Cited by 10 · see citing works
“Each mutant KRAS structure was modeled bound to GTP-Mg 2 + by fitting the 6OB2 [12] GDP-PnP to GDP and converting it into GTP.”
A RhoA structure with switch II flipped outward revealed the conformational dynamics of switch II region
Jiang, H., Zu, S., Lu, Y., Sun, Z., Adeerjiang, A., Guo, Q., Zhang, H., Chen, D., Wu, Q., Ding, H., et al. (2023) · Journal of Structural Biology · doi:10.1016/j.jsb.2023.107942 · Cited by 9 · see citing works
Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex
Damianou, A., Liang, Z., Lassen, F. H., Vendrell, I., Vere, G., Hester, S., Charles, P. D., Pinto-Fernández, A., Santos, A., Fischer, R., et al. (2024) · Life Science Alliance · doi:10.26508/lsa.202302245 · Cited by 9 · see citing works
Monoubiquitination of KRAS at Lysine104 and Lysine147 Modulates Its Dynamics and Interaction with Partner Proteins
Nair, V. V., Yin, G., Zhang, J., Hancock, J. F., Campbell, S. L., & Gorfe, A. A. (2021) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.1c01062 · Cited by 9 · see citing works
Inhibition of colon cancer K-RasG13D mutation reduces cancer cell proliferation but promotes stemness and inflammation via RAS/ERK pathway
Yan, Q., Zou, H., Zhao, X., Kapeleris, J., Monteiro, M. J., Li, F., Xu, Z. P., Deng, Y., Wu, Y., Tang, Y. F., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.996053 · Cited by 9 · see citing works
RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation
Chippalkatti, R., Parisi, B., Kouzi, F., Laurini, C., Fredj, N. B., & Abankwa, D. (2024) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2024.151425 · Cited by 8 · see citing works
Targeting the HER2-ELF3-KRAS axis: a novel therapeutic strategy for KRASG13D colorectal cancer
Hwang, S., Seo, Y., Park, S., Kim, S.-A., Moon, I., Liu, Y., Kim, S., Pak, E. S., Jung, S., Kim, H., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02343-5 · Cited by 8 · see citing works
“KRAS G13D cancers retain some regulatory capabilities similar to KRAS WT cancers due to their intermediate sensitivity to NF1 (neurofibromin)-mediated GTP hydrolysis, unlike KRAS G12 mutations, which are largely insensitive to this process [9].”
The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells
Tisi, R., Spinelli, M., Palmioli, A., Airoldi, C., Cazzaniga, P., Besozzi, D., Nobile, M. S., Mazzoleni, E., Arnhold, S., GIOIA, L. D., et al. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.625979 · Cited by 8 · see citing works
“Structural and functional studies (Smith et al., 2013; Hunter et al., 2015; Lu et al., 2016b; Johnson et al., 2019; Rabara et al., 2019) indicate that this mutant remains sensitive to the catalytic activity of GEFs and of at least one GAP, Nf1.”
BackgroundMethod
Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein
Polyakov, I. V., & Nemukhin, A. V. (2023) · Biophysica · doi:10.3390/biophysica3020025 · Cited by 7 · see citing works
YB-1 activating cascades as potential targets in KRAS-mutated tumors
Khozooei, S., Veerappan, S., & Toulany, M. (2023) · Strahlentherapie und Onkologie · doi:10.1007/s00066-023-02092-8 · Cited by 6 · see citing works
“An in vitro study has shown that G13 mutations are relatively susceptible to targeting EGFR when compared to G12 mutations [162].”
Background
PTEN Oxidation Promotes Constitutive PI3K Signaling and Inducible Macropinocytosis in Pancreatic Cancer
Burge, R. A., Bialousow, L., Linke, A. J., Coalson, H. S., Adair, S. J., Sundararaj, K. P., Smith, M., Bumbleburg, C., Bauer, T. W., Kashatus, D. F., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-4501 · Cited by 6 · see citing works
Enhancing Characteristic Gene Selection and Tumor Classification by the Robust Laplacian Supervised Discriminative Sparse PCA
Zhang, L.-X., Yan, H., Liu, Y., Xu, J., Song, J., & Yu, D. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c01403 · Cited by 6 · see citing works
GAP positions catalytic H-Ras residue Q61 for GTP hydrolysis in molecular dynamics simulations, complicating chemical rescue of Ras deactivation
Patel, L. A., Waybright, T. J., Stephen, A. G., & Neale, C. (2023) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2023.107835 · Cited by 6 · see citing works
Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion
Lazarte, J. M. S., & Lamango, N. S. (2024) · Biomedicines · doi:10.3390/biomedicines12030470 · Cited by 6 · see citing works
“…GTPase activity and thus drives only about 5% of breast cancer cases, the downregulation of RASA1, which is the GTPase-activating protein (GAP) that promotes KRAS deactivation through GTP hydrolysis [25,26], implies that KRAS is a significant contributor to cancer progression in 77% of TNBC.”
Background
Structural modifications and kinetic effects of KRAS interactions with HRAS and NRAS: an in silico comparative analysis of KRAS mutants
Silverman, I., Gerber, M. A., Shaykevich, A., Stein, Y. F., Siegman, A., Goel, S., & Maitra, R. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1436976 · Cited by 6 · see citing works
The isolated GTPase-activating-protein-related domain of neurofibromin-1 has a low conformational stability in solution
Neira, J. L., Vega, S., Martínez‐Rodríguez, S., & Velázquez‐Campoy, A. (2021) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2021.108767 · Cited by 6 · see citing works
Progress in Targeting KRAS Directly
Nissley, D. V., Stephen, A. G., Yi, M., & McCormick, F. P. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-3822-4_1 · Cited by 6 · see citing works
Self-citation
GAP mimetic activity of pan-Ras TCI daraxonrasib synergizes with K-Ras Switch-II pocket inhibition
Pfaff, P., & Shokat, K. M. (2026) · Biological Chemistry · doi:10.1515/hsz-2025-0249 · Cited by 5 · see citing works
“Interestingly, in a structure that displays an inactive conformation of NF1 bound to Ras (Rabara et al. 2019) (Figure 1D), the catalytic Arg remains in a distal position to the active site and access to the γ -phosphate is blocked by Tyr32 (highlighted in red).”
Colorectal cancer cells with high metastatic potential drive metastasis by transmitting exosomal miR-20a-3p through modulating NF1/MAPK pathway
Liang, Y., Li, J., Li, T., Li, M., Liao, H., Liu, Y., Yao, Y., Yang, L., & Lei, X. (2024) · Carcinogenesis · doi:10.1093/carcin/bgae036 · Cited by 5 · see citing works
Mortality Outcome Associated with Specific KRAS, NRAS, and BRAF Hot-Spot Mutations in Metastatic Colorectal Cancer Patients: A Retrospective Cohort Study
Abdelgadir, O., Kuo, Y., Khan, M. F., Okorodudu, A. O., Cheng, Y., & Dong, J. (2025) · Diagnostics · doi:10.3390/diagnostics15050590 · Cited by 5 · see citing works
“This suggests that tumors harboring KRAS c.38G>A (p.Gly13Asp) might be more responsive to anti-EGFR monoclonal antibody therapy [42].”
Distal Covalent Targeting Suppresses Signaling of Oncogenic K-Ras(G13C) in Cancer Cells
Zheng, Q., Shen, T., Pampel, J., & Shokat, K. M. (2025) · ACS Chemical Biology · doi:10.1021/acschembio.5c00249 · Cited by 4 · see citing works
Identification of key miRNAs and their targets in peripheral blood mononuclear cells of IgA nephropathy using bioinformatics analysis
Liu, L., Yang, Y., & Yu, D. (2021) · Medicine · doi:10.1097/md.0000000000026495 · Cited by 4 · see citing works
“KRAS gene can active MAPK pathway and then participate in a variety of physiological processes.([19,22]) MAPK pathways are likely form the basis of IgAN progression.”
Background
Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia
Wang, H., Moniruzzaman, R., Li, L., Ji, B., Liu, Y., Zuo, X., Abbasgholizadeh, R., Zhao, J., Liu, G., Wang, R. L., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci163873 · Cited by 4 · see citing works
Structurally-informed human interactome reveals proteome-wide perturbations by disease mutationsPreprint
Xiong, D., Qiu, Y., Zhao, J., Zhou, Y., Lee, D., Gupta, S., Torres, M., Lü, W., Liang, S., Kang, J. J., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.24.538110 · Cited by 4 · see citing works
KRAS mutations in colorectal cancer: impacts on tumor microenvironment and therapeutic implications
Emami, A., Sharif, P. M., & Rezaei, N. (2025) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2025.2500426 · Cited by 3 · see citing works
“KRAS G13D -mutated cells are often co-mutated with the GAP family member neurofibromin 1 (NF1, which hydrolyzes GTP directly in collaboration with KRAS G13D ) rather than KRAS G12 and KRAS Q61 , suggesting that cetuximab may be beneficial for NF1-KRAS G13 co-mutated CRCs [67].”
Single-molecule imaging quantifies oncogenic KRAS dynamics for enhanced accuracy of therapeutic efficacy assessment
Yokoi, R., Mori, T., Hirosawa, K. M., Kondo, R., Taguchi, T., Matsuhashi, N., & Suzuki, K. G. N. (2025) · iScience · doi:10.1016/j.isci.2025.113374 · Cited by 3 · see citing works
“7,26,66 Before EGF stimulation, the temporal fraction of KRAS G13D trapping was comparable to that of G12D and G12C (5.6%–6.1”
Influential
Methods to Monitor Ras Activation State
Kopra, K., & Härmä, H. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1190-6_8 · Cited by 3 · see citing works
Drugging the undruggable: Advances in targeting KRAS signaling in solid tumors
Tripathi, P., Kumari, R., & Pathak, R. (2024) · International review of cytology · doi:10.1016/bs.ircmb.2023.11.004 · Cited by 3 · see citing works
Therapeutic Targeting of RAS Mutant Cancers
Stites, E. C., Paskvan, K. V., & Kato, S. (2022) · Cambridge University Press eBooks · doi:10.1017/9781009064828 · Cited by 2 · see citing works
Discovery of nonautonomous modulators of activated Ras
Corchado-Sonera, M., Rambani, K., Navarro, K., Kladney, R. D., Dowdle, J. A., Leone, G. W., & Chamberlin, H. (2022) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkac200 · Cited by 3 · see citing works
“For example, human tumors bearing KRasG13D are sensitive to EGFR inhibitors, whereas KRasG12D or G12V are not (De Roock et al. 2010; Rabara et al. 2019; Zafra et al. 2020; McFall and Stites 2021). szy-5 encodes a zinc finger protein, with 2 canonical tripleC2H2 domains (Wolfe et al. 2000; Iuchi…”
Background
The cryo-EM structure of the neurofibromin dimer reveals the molecular basis for von Recklinghausen diseasePreprint
Lupton, C. J., Bayly-Jones, C., D’Andrea, L., Huang, C., Schittenhelm, R. B., Venugopal, H., Whisstock, J. C., Halls, M. L., & Ellisdon, A. M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.18.431788 · Cited by 3 · see citing works
Interplay Between KRAS and LZTR1 Protein Turnover, Controlled by CUL3/LZTR1 E3 Ubiquitin Ligase, is Disrupted by KRAS MutationsPreprint
Damianou, A., Liang, Z., Lassen, F. H., Vere, G., Hester, S., Charles, P. D., Pinto-Fernández, A., Santos-Delgado, A., Fischer, R., & Kessler, B. M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.23.469679 · Cited by 3 · see citing works
“…NF1 and SPRED2 are only enriched with the G13D and Q61H mutants, but not with G12D, suggesting that G13D and Q61H are associated with NF1/SPRED2 to a greater extent as compared to G12D, consistent with previous findings reporting that NF1 is not able to affect G12D KRAS (Rabara et al., 2019).”
ResultInfluential
Pancreatic Cells Are Resistant to KRASQ61L Expression due to Hyperactive ERK/MAPK Signaling and Apoptosis Induction
Burge, R. A., Bialousow, L., McFall, T. B., Bamonte, L., Johnson, G., Smith, M., Vaena, S. G., Comte‐Walters, S., Ball, L. E., Berto, S., et al. (2025) · Cancer Research Communications · doi:10.1158/2767-9764.crc-25-0281 · Cited by 2 · see citing works
Functional Analysis of Rare RAS Variants of Unknown Significance
Park, S., Ikegami, M., Kitada, R., Takamochi, K., Suzuki, K., Mano, H., & Kohsaka, S. (2025) · Cancer Research Communications · doi:10.1158/2767-9764.crc-25-0188 · Cited by 2 · see citing works
“However, the significance of KRAS mutants’ cycle between the “on” and “off” states and depend on nucleotide exchange for their activation (18, 49, 50).”
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McCormick, F. P. (2026) · Biological Chemistry · doi:10.1515/hsz-2025-0244 · Cited by 2 · see citing works
Self-citation

Abstract B03: Biologic and biochemical interactions of NF1 GAP on KRAS G13x mutations
Rabara, D., Stephens, R. M., & Holderfield, M. T. (2020) · Molecular Cancer Research · doi:10.1158/1557-3125.ras18-b03
Self-citation
Discernment between candidate mechanisms for KRAS G13D colorectal cancer sensitivity to EGFR inhibitors
McFall, T. B., Schomburg, N. K., Rossman, K. L., & Stites, E. C. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00645-3 · Cited by 25 · see citing works
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Stites, E. C., & McFall, T. B. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2019.11.2515
A systems mechanism for KRAS mutant allele–specific responses to targeted therapy
McFall, T., Diedrich, J. K., Mengistu, M., Littlechild, S. L., Paskvan, K. V., Sisk-Hackworth, L., Moresco, J. J., Shaw, A. S., & Stites, E. C. (2019) · Science Signaling · doi:10.1126/scisignal.aaw8288 · Cited by 65 · see citing works
A mechanism for the response of KRASG13D expressing colorectal cancers to EGFR inhibitors
McFall, T. B., & Stites, E. C. (2020) · Molecular & Cellular Oncology · doi:10.1080/23723556.2019.1701914 · Cited by 14 · see citing works

Authors: Rabara, D., Tran, T. H., Dharmaiah, S., Stephens, R. M., McCormick, F., Simanshu, D. K., & Holderfield, M.
Affiliations: Frederick National Laboratory for Cancer Research (US)
University of California, San Francisco (US)
ORCID: Rabara, Dana
Tran, Timothy H.
Dharmaiah, Srisathiyanarayanan
McCormick, Frank
Simanshu, Dhirendra K.
Holderfield, Matthew
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2019-10-14
Volume: 116
Issue: 44
Pages: 22122-22131
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1908353116
PMC: PMC6825300
OpenAlex: W2980433900
Cited by: 128
References: 39
Citations by year: 2026: 13 · 2025: 17 · 2024: 18 · 2023: 16 · 2022: 26 · 2021: 23 · 2020: 14 · 2019: 1
FWCI: 5.29
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 183 d)
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders: HHS | NIH | National Cancer Institute (HHSN2612000800001E, P41 GM103403)
U.S. Department of Energy (DE-AC02-06CH11357)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: KRAS G13D mutation, neurofibromin, GTP hydrolysis, colorectal cancer, EGFR inhibitors, MAPK signaling, protein-protein complex structure, co-occurring mutations
MeSH terms: Antineoplastic Agents, Cell Line, Guanosine Triphosphate, Humans, Hydrolysis, Models, Molecular, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Amino Acid Substitution, Catalytic Domain, GTPase-Activating Proteins, Neurofibromin 1, Protein Kinase Inhibitors, ErbB Receptors

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KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

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