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A Comprehensive Survey of Ras Mutations in Cancer
Open accessAbstract
All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, and N-Ras, that promote oncogenesis when they are mutationally activated at codon 12, 13, or 61. Although there is a high degree of similarity among the isoforms, K-Ras mutations are far more frequently observed in cancer, and each isoform displays preferential coupling to particular cancer types. We examined the mutational spectra of Ras isoforms curated from large-scale tumor profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino-acid substitution biases. These findings were unexpected given that these mutations occur in regions that share 100% amino-acid sequence identity among the 3 isoforms. Of importance, many of these mutational biases were not due to differences in exposure to mutagens, because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms, as well as isoform-specific differences in protein structure and signaling, that may promote these distinct mutation patterns and differential coupling to specific cancers. Cancer Res; 72(10); 2457–67. ©2012 AACR.
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“Approximately 90% of PDAC cases harbor a Kirsten rat sarcoma (KRAS) mutation (Prior et al., 2012).”
From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Prior et al., 2012
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“This specific mutation, present in ~3% of CRC cases, 2 is associated with significantly reduced progression-free survival (PFS) and overall survival (OS) compared to KRAS wildtype tumors.[3][4][5]”
From Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation (2025) · cites this paper as [2]
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“Unlike other clinically actionable genomic alterations found in NSCLCs (such as EGFR and ALK aberrations), KRAS mutations, particularly KRASG12C and KRASG12V, are strongly associated with smoking29–31.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [29]
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“However, RAS mutations and the resulting deregulated signaling events are responsible for one third of all human cancers4 (Figure 1).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [4]
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“Overall, KRAS is mutated in many cancers (predominantly adenocarcinomas), whereas NRAS mutations are prominent in melanoma and myeloid cancer4,15,16 (Fig. 1).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [4]
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“The basis of the specific G12X mutation frequencies has remained unclear, except for the G12C transversion mutation (c.34G>T) associated with smoking in lung cancer [6,7].”
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BackgroundMethodInfluentialCrosstalk between Rac1-mediated actin regulation and ROS production
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“The RAS family has three major isoforms, KRAS, HRAS and NRAS (Barbacid, 1987; Malumbres and Barbacid, 2003) that share 92-98% sequence identity in their amino-terminal region, and oncogenic mutations of RAS family members are commonly found in 20% to 30% of all human tumors (Prior et al., 2012; Stephen et al., 2014).”
Inhibition of RAF dimers: it takes two to tango
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“KRAS, a small GTPase that activates MAPK signaling, is one of the most frequently mutated driver oncogenes (1).”
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“These results are nearly the mirror image of the development of pancreatic pathologies and PDAC upon endogenous FGF21 loss under similar conditions [32], indicating an important lifelong role of FGF21 in limiting the development of metabolic abnormalities and associated organ pathologies that can progress to a long-te…”
BackgroundInfluentialStaurosporines Disrupt Phosphatidylserine Trafficking and Mislocalize Ras Proteins
Cho, K.-J., Park, J.-H., Piggott, A. M., Salim, A. A., Alemayehu, A. G., Parton, R. G., Capon, R. J., Lacey, E., & Hancock, J. F. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.424457 · Cited by 94
“Oncogenic Ras proteins, expressed in 15% of all human tumors, are major drivers of transformation (15), with the predominant clinical problem being mutant K-Ras (15, 16).”
BackgroundDeactivation Pathway of Ras GTPase Underlies Conformational Substates as Targets for Drug Design
Lu, S., Ni, D., Wang, C., He, X., Lin, H., Wang, Z., & Zhang, J. (2019) · ACS Catalysis · doi:10.1021/acscatal.9b02556 · Cited by 90
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“However, there is little understanding of the factors leading to the isoform-specific preferences associated with Ras oncogenic mutants, and, in spite of great need, there are no US Food and Drug Administration (FDA)approved inhibitors of Ras available in the clinic (Haigis, 2017; Prior et al., 2012).”
BackgroundSelf-citationDiscovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding
McCarthy, M. J., Pagba, C. V., Prakash, P., Naji, A. K., van der Hoeven, D., Liang, H., Gupta, A. K., Zhou, Y., Cho, K.-J., Hancock, J. F., et al. (2019) · ACS Omega · doi:10.1021/acsomega.8b03308 · Cited by 90
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“Activating mutations at codons 12, 13, nd 61 [2] promote oncogenesis.”
BackgroundHRAS Mutations in Epithelial–Myoepithelial Carcinoma
Chiosea, S. I., Miller, M., & Seethala, R. R. (2013) · Head and Neck Pathology · doi:10.1007/s12105-013-0506-4 · Cited by 90
“For instance, while KRAS mutations predominate in lung and colon adenocarcinomas, HRAS (Harvey rat sarcoma viral oncogene homolog) mutations are overrepresented in salivary gland tumors as per the COSMIC dataset [1] and present in about 15 % of salivary cancers as a whole [1].”
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“%) mutations are most common in PDAC (4).”
Kirsten Ras* oncogene: Significance of its discovery in human cancer research
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“Indeed, KRAS mutations occur in 22% of all tumors analyzed (the highest among RAS isoforms), while HRAS and NRAS mutations are less frequent (3% and 8%, respectively) [2].”
BackgroundDirect inhibition of RAS: Quest for the Holy Grail?
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“3B).(5,30) KRAS mutations, in contrast, account for nearly 85% of all RAS mutations in human tumors, with nearly 100% of pancreatic ductal adenocarcinoma possessing mutant KRAS alleles.”
BackgroundAtypical BRAF and NRAS Mutations in Mucosal Melanoma
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“three forms of RAS, mutations are most frequently found in KRAS (85%), followed by NRAS (12%) and HRAS (3%).(9,16) In KRAS, mutations are found almost exclusively in codons 12, 13 and 61, corresponding to”
BackgroundInfluentialRas and the Plasma Membrane: A Complicated RelationshipPreprint
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“Prototypical examples are the three Ras isoforms that are ubiquitously expressed in human cells: K-, H-, and N-Ras, of which K-Ras and N-Ras are frequently mutated in human cancers (Prior et al. 2012).”
BackgroundStrategies to tackle RAS-mutated metastatic colorectal cancer
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“The RAS family is one of the most frequently mutated across all malignancies, including CRC.(11) Indeed, around 40% of CRC harbors KRAS mutations plus an additional 4% NRAS mutations (and a negligible <1% prevalence of HRAS mutations), with >95% of them occurring in KRAS G12, G13, or Q61 codons.”
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“The most interesting aspect of Ras biology is it being the most frequently mutated oncogene (see Prior et al., 2012, for a complete list of mutations).”
BackgroundChanneling the Force: Piezo1 Mechanotransduction in Cancer Metastasis
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Posttranslational Modifications of RAS ProteinsPreprint
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“Modern cancer genome analysis has confirmed that the three human RAS genes, KRAS, NRAS, andHRAS, are mutated in cancer more frequently than any other oncogene (Forbes et al. 2011; Prior et al. 2012).”
BackgroundPantsar, T., Rissanen, S., Dauch, D., Laitinen, T., Vattulainen, I., & Poso, A. (2018) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1006458 · Cited by 85
“34G>T) associated with smoking in lung cancer [6,7].”
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Self-citationTargeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity
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“The three closely related RAS proteins (HRAS, KRAS, NRAS) promote oncogenesis when mutated at codon 12, 13 or 61 [27].”
Lu, S., Banerjee, A., Jang, H., Zhang, J., Gaponenko, V., & Nussinov, R. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.664755 · Cited by 86
“frequently mutated isoform in Ras-driven cancers followed by N-Ras (11%) and H-Ras (3%) (13).”
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“The upstream activators of PI3Ks are also frequently misregulated in cancer, with the KRas isoform of Ras being the most frequently mutated oncogene in all human cancers (8, 9).”
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A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers
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“Activating RAS mutations are found in around 30% of all human cancers.(3,4) Among the three RAS genes, mutation frequency of KRAS in human cancer is considerably higher than that of HRAS and NRAS.”
BackgroundTargeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS
Yin, G., Huang, J., Petela, J., Jiang, H., Zhang, Y., Gong, S., Wu, J., Liu, B., Shi, J., & Gao, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01441-4 · Cited by 98
“The most commonly mutated residues in Ras proteins include G12, G13, and Q61, as these mutants impede GTP hydrolysis and lead to constitutive activation of Ras.213 In addition to tumors, RASopathies are a group of genetic disorders caused by germline mutations in genes that encode proteins of RAS/MAPK pathway and thei…”
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“The frequency of RAS mutations in thyroid cancer is reported to be about 14%, and many thyroid cancers carry mutations in all three isoforms (1).”
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“Because Ras-dependent cancers most often harbor a mutation in kras (2), unique properties of the K-Ras proteins may prove useful in developing anti-Ras therapeutics.”
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KRAS G12C Mutations in NSCLC: From Target to Resistance
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“Three factors may participate in creating the right circumstances for the development and progression of Ras-driven tumours according to each tumour type[19].”
BackgroundMAPK kinase signalling dynamics regulate cell fate decisions and drug resistance
Rauch, N., Rukhlenko, O. S., Kölch, W., & Kholodenko, B. Ν. (2016) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.07.019 · Cited by 86
“About 30% of all human cancers, including about 90% of pancreatic cancer and 45% of colorectal cancer cases, present activating mutations in RAS family genes (HRAS, K-RAS, and N-RAS) [21], with K-RAS being the most frequently mutated isoform [22].”
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High-affinity interaction of the K-Ras4B hypervariable region with the RAS active site
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“Such constitutively activated Ras (especially K-Ras mutations at residue G12) are often overexpressed in many different types of cancer cells (accounting for 30% human cancers) (Bryant et al., 2014; Prior et al., 2012; Schubbert et al., 2007).”
Sarkar‐Banerjee, S., Sayyed–Ahmad, A., Prakash, P., Cho, K., Waxham, M. N., Hancock, J. F., & Gorfe, A. A. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b06292 · Cited by 78
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The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy
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“Approximately 99% of RAS mutations involve codons 12, 13 or 61 [26,27].”
BackgroundDifferential Reprogramming of Isogenic Colorectal Cancer Cells by Distinct Activating KRAS Mutations
Hammond, D. E., Mageean, C. J., Rusilowicz, E. V., Wickenden, J. A., Clague, M. J., & Prior, I. A. (2015) · Journal of Proteome Research · doi:10.1021/pr501191a · Cited by 81
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“myoepithelial carcinoma, and kidney cancers (25, 26).”
Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Tang, D., Kroemer, G., & Kang, R. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01422-7 · Cited by 80
Flux: Overcoming scheduling challenges for exascale workflows
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Nonredundant Functions for Ras GTPase-Activating Proteins in Tissue Homeostasis
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“Mutations at Gln(61) or at residues 12 or 13, which alter the orientation of Gln(61), prevent GTP hydrolysis, which locks Ras in a permanently “on” state (9, 10).”
BackgroundAutophagy role(s) in response to oncogenes and DNA replication stress
Vanzo, R., Bartkova, J., Merchut-Maya, J. M., Hall, A., Bouchal, J., Dyrskjøt, L., Frankel, L. B., Gorgoulis, V., Maya-Mendoza, A., Jäättelä, M., et al. (2020) · Cell Death & Differentiation · doi:10.1038/s41418-019-0403-9 · Cited by 79
Cao, Y., Wang, X., Li, Y., Evers, M., Zhang, H., & Chen, X. (2019) · Cancer Cell International · doi:10.1186/s12935-019-0973-0 · Cited by 77
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
Molecular Defects in Mastocytosis
Bibi, S., Langenfeld, F., Jeanningros, S., Brenet, F. A., Soucie, E. L., Hermine, O., Damaj, G. L., Dubreuil, P. C., & Arock, M. (2014) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2014.01.009 · Cited by 79
The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas
Nussinov, R., Muratcioğlu, S., Tsai, C., Jang, H., Gürsoy, A., & Keskin, Ö. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0165 · Cited by 78
“PDAC is complex and heterogeneous (26, 33 – 38) and the key mutations may differ (22, 26, 39 – 43).”
BackgroundInfluentialLohinai, Z., Klikovits, T., Moldvay, J., Ostoros, G., Rásó, E., Tı́már, J., Fábián, K., Kovalszky, I., Kenessey, I., Aigner, C., et al. (2017) · Scientific Reports · doi:10.1038/srep39721 · Cited by 78
Nelson-Taylor, S. K., Le, A. T., Yoo, M., Schubert, L., Mishall, K. M., Doak, A. E., Varella‐Garcia, M., Tan, A. C., & Doebele, R. C. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0008 · Cited by 79
“It is interesting that mutations in NRAS, and not KRAS, are increasingly being identified as mechanisms of resistance to TKI therapy in NSCLC, despite the fact that KRAS is a far more common primary oncogenic driver of NSCLC (48).”
Real world outcomes in KRAS G12C mutation positive non-small cell lung cancer
Cui, W., Franchini, F., Alexander, M., Officer, A., Wong, H., IJzerman, M. J., Desai, J., & Solomon, B. (2020) · Lung Cancer · doi:10.1016/j.lungcan.2020.06.030 · Cited by 80
“[1,2]] KRAS is the most prevalent KRAS mutation, and has been identified in approximately 15 % of NSCLC.”
BackgroundSingh, A. V., Bhardwaj, P., Laux, P., Pradeep, P., Busse, M., Luch, A., Hirose, A., Osgood, C. J., & Stacey, M. W. (2024) · Frontiers in Toxicology · doi:10.3389/ftox.2024.1461587 · Cited by 84
“For instance, mutations in the RAS family of proto-oncogenes can lead to constitutive activation of RAS signaling pathways, promoting cell proliferation and survival (Prior et al., 2012).”
Calmodulin and PI3K Signaling in KRAS Cancers
Nussinov, R., Wang, G., Tsai, C., Jang, H., Lu, S., Banerjee, A., Zhang, J., & Gaponenko, V. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.01.007 · Cited by 78
“KRAS is among the most frequently mutated oncogenes in human tumors [8–12], particularly in pancreatic (almost 100%), lung (35%), and colorectal (45%) cancers [13,14].”
Recurrent KRAS mutations in papillary renal neoplasm with reverse polarity
Al‐Obaidy, K. I., Eble, J. N., Nassiri, M., Liang Cheng, C., Eldomery, M. K., Williamson, S. R., Sakr, W., Gupta, N., Hassan, O., Idrees, M. T., et al. (2019) · Modern Pathology · doi:10.1038/s41379-019-0362-1 · Cited by 79
Direct Modulation of Small GTPase Activity and Function
Cromm, P. M., Spiegel, J., Grossmann, T. N., & Waldmann, H. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201504357 · Cited by 80
SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways
Bottino, C., Peserico, A., Simone, C., & Caretti, G. (2020) · Cancers · doi:10.3390/cancers12010142 · Cited by 78
“SMYD3 over-expression has been described especially in cancer types carrying K-Ras mutations and since the k-Ras mutations occur in more than a half of human cancers, the link to SMYD3 is clinically very relevant [46,47].”
BackgroundDrugging All RAS Isoforms With One Pocket
Kessler, D., Bergner, A., Böttcher, J., Fischer, G., Döbel, S., Hinkel, M., Müllauer, B., Weiss-Puxbaum, A., & McConnell, D. B. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0221 · Cited by 75
Nagasaka, M., Potugari, B. R., Nguyen, A., Sukari, A. W., Azmi, A. S., & Ou, S. I. (2021) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2021.102309 · Cited by 80
MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer
Casacuberta‐Serra, S., González-Larreategui, Í., Capitán-Leo, D., & Soucek, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01907-z · Cited by 84
The higher level of complexity of K‐Ras4B activation at the membrane
Jang, H., Banerjee, A., Chavan, T., Lu, S., Zhang, J., Gaponenko, V., & Nussinov, R. (2015) · The FASEB Journal · doi:10.1096/fj.15-279091 · Cited by 75
“Kirsten Ras viral oncogene homolog (KRAS) is a frequently mutated oncogene in Ras-driven cancers (3).”
BackgroundDrugging K-RasG12C through covalent inhibitors: Mission possible?
Ni, D., Li, X., He, X., Zhang, H., Zhang, J., & Lu, S. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.06.007 · Cited by 73
Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects
Marcus, K., & Mattos, C. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2148 · Cited by 75
“Contrary to what is observed in all other oncogenic mutants, the water-mediated network from the g-phosphate to the nucleotide sensing residues in helix 5 is intact in both structures ofRASG12D, and thismay contribute to the effectiveness and frequency of this mutant in human cancers (20, 28).”
BackgroundSelf-citationTherapeutics Targeting Mutant KRAS
Thein, K. Z., Biter, A. B., & Hong, D. S. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-080819-033145 · Cited by 76
Melanogenesis and the Targeted Therapy of Melanoma
Li, C., Kuai, L., Cui, R., & Miao, X. (2022) · Biomolecules · doi:10.3390/biom12121874 · Cited by 83
Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells
Mason, J. A., Davison-Versagli, C. A., Leliaert, A. K., Pape, D. J., McCallister, C. M., Zuo, J.-L., Durbin, S., Buchheit, C. L., Zhang, S., & Schafer, Z. T. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.15 · Cited by 72
Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells
Yoh, K. E., Regunath, K., Guzman, A., Lee, S.-M., Pfister, N. T., Akanni, O., Kaufman, L. J., Prives, C., & Prywes, R. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613417113 · Cited by 75
“Proc Natl Acad Sci USA 102(3):802–807.”
BackgroundInfluentialPrecision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles
Strand, M. S., Krasnick, B. A., Pan, H., Zhang, X., Bi, Y., Brooks, C., Wetzel, C., Sankpal, N., Fleming, T., Goedegebuure, S. P., et al. (2019) · Oncotarget · doi:10.18632/oncotarget.27109 · Cited by 74
“Collectively, these small GTPases represent the most frequently mutated oncogene family in human cancer, present in up to 30% of all cases [1].”
BackgroundGalectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering
Blaževitš, O., Mideksa, Y. G., Šolman, M., Ligabue, A., Ariotti, N., Nakhaeizadeh, H., Fansa, E. K., Papageorgiou, A. C., Wittinghofer, A., Ahmadian, M. R., et al. (2016) · Scientific Reports · doi:10.1038/srep24165 · Cited by 74
Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane
Fang, Z., Lee, K., Huo, K.-G., Gasmi-Seabrook, G. M. C., Zheng, L., Moghal, N., Tsao, M., Ikura, M., & Marshall, C. B. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1914076117 · Cited by 74
“Marius Clore, Practical aspects of (1)H transverse paramagnetic”
BackgroundMolecules linked to Ras signaling as therapeutic targets in cardiac pathologies
Ramos-Kuri, M., Meka, S. H., Salamanca‐Buentello, F., Hajjar, R. J., Lipskaia, L., & Chemaly, E. R. (2021) · Biological Research · doi:10.1186/s40659-021-00342-6 · Cited by 73
“This proliferative role of K-Ras is also observed in other tissues: mutations of K-Ras are associated with 25–30% of all cancers, versus 3% for H-Ras and 8% for N-Ras [4].”
BackgroundInfluentialBoppudi, S., Bögershausen, N., Hove, H., Perçin, E. F., Aslan, D., Dvorský, R., Kayhan, G., Li, Y., Cursiefen, C., Tantcheva‐Poór, I., et al. (2016) · Clinical Genetics · doi:10.1111/cge.12775 · Cited by 74
“This hypothesis is further supported by the observation that specific oncogenic RAS mutations also display differential coupling to specific cancers (31).”
BackgroundMetabolic rewiring in mutant Kras lung cancer
Kerr, E. M., & Martins, C. P. (2017) · FEBS Journal · doi:10.1111/febs.14125 · Cited by 76
Post-Translational Peptide Splicing and T Cell Responses
Mishto, M., & Liepe, J. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.07.011 · Cited by 76
Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer
Wan, L., Lin, K., Rahman, M. A., Ishigami, Y., Wang, Z., Jensen, M. A., Wilkinson, J. E., Park, Y., Tuveson, D. A., & Krainer, A. R. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1013 · Cited by 72
Cserepes, M., Ostoros, G., Lohinai, Z., Rásó, E., Barbai, T., Tı́már, J., Rózsás, A., Moldvay, J., Kovalszky, I., Fábián, K., et al. (2014) · European Journal of Cancer · doi:10.1016/j.ejca.2014.04.001 · Cited by 75
“In the latter, the mutation rate was found to be up to 30% [4,5].”
BackgroundProtein Domain-Level Landscape of Cancer-Type-Specific Somatic Mutations
Yang, F., Petsalaki, E., Rolland, T., HILL, D. E., Vidal, M., & Roth, F. P. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004147 · Cited by 71
“Enrichment of somatic mutations within Ras domains has been reported for different individual genes[61, 62].”
BackgroundPI3K: A Crucial Piece in the RAS Signaling PuzzlePreprint
Krygowska, A. A., & Castellano, E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031450 · Cited by 79
“Point mutations in certain amino acid residues, most commonly at positions G12, G13, and Q61, lead to the expression of constitutively active proteins (Bos 1989; Prior et al. 2012) that signal to downstream effectors even in the absence of extracellular stimuli (Barbacid 1987; Riely et al. 2009).”
BackgroundInhibitors of Ras–SOS Interactions
Lu, S., Jang, H., Zhang, J., & Nussinov, R. (2016) · ChemMedChem · doi:10.1002/cmdc.201500481 · Cited by 72
Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts
Dunnett-Kane, V., Burkitt-Wright, E., Blackhall, F. H., Malliri, A., Evans, D. G., & Lindsay, C. R. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.03.291 · Cited by 66
“This isoform bias is striking considering that the RAS isoforms are virtually identical in structure beyond their hypervariable domain, and that these mutations occur in regions that are identical in their amino acid sequence.(6) RAS activation in cancer can occur through other mechanisms, including disruption of GAPs…”
BackgroundPeriodontal Pathogens in the Etiology of Pancreatic Cancer
Öğrendik, M. (2016) · Gastrointestinal Tumors · doi:10.1159/000452708 · Cited by 72
Functional Genomics for Cancer Drug Target Discovery
Haley, B., & Roudnicky, F. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.04.006 · Cited by 75
Drugging the Undruggable: Advances on RAS Targeting in Cancer
Molina‐Arcas, M., Samani, A., & Downward, J. (2021) · Genes · doi:10.3390/genes12060899 · Cited by 76
“Mutations in RAS genes occur frequently in solid and haematological malignancies with around 20% of all tumours harbouring a mutation in at least one isoform [1,2].”
BackgroundRegulation of cell signaling pathways by dietary agents for cancer prevention and treatment
Pandey, M. K., Gupta, S. C., Nabavizadeh, A., & Aggarwal, B. B. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.07.002 · Cited by 73
“activated Ras protein influences several aspects of tumorigenesis such as aberrant cell growth, cell death, invasiveness, and angiogenesis [154, 155].”
Background
Metadata
- Authors
- Prior, I. A., Lewis, P. D., & Mattos, C.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Prior, Ian A.
- Venue
- Cancer Research
- Published
- 2012-05-14
- Volume
- 72
- Issue
- 10
- Pages
- 2457-2467
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3354961
- OpenAlex
- W2135184154
- Cited by
- 2,063
- References
- 67
- Citations by year
- 2026: 114 · 2025: 154 · 2024: 169 · 2023: 203 · 2022: 189 · 2021: 223 · 2020: 203 · 2019: 164 · 2018: 162 · 2017: 144 · 2016: 110 · 2015: 111 · 2014: 52 · 2013: 47 · 2012: 13
- FWCI
- 23.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (067398)
- Cancer Research UK (A6672)
- Biotechnology and Biological Sciences Research Council (BB/G018162/1)
- National Cancer Institute (R56CA096867)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- RAS mutations, KRAS, H-Ras, NRAS, Ras isoforms, codon 12 mutation, mutational spectra, carcinogenesis, epigenetic mechanisms, Ras signaling
- MeSH terms
- Cell Transformation, Neoplastic, Codon, Humans, Models, Molecular, Molecular Conformation, Neoplasms, Genes, ras, Signal Transduction, Point Mutation, ras Proteins, Protein Isoforms, Catalytic Domain, Databases, Genetic, Epigenesis, Genetic
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