Cited by 1,902Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

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RAS oncogenes: the first 30 years

Malumbres, Marcos, Barbacid, Mariano·2003·Nature Reviews Cancer

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Abstract

From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction - mainly in human cancer - is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.

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Background
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Background
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Background
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“Ras proteins are small GTPases involved in the regulation of important cellular functions such as proliferation, differen tiation, and apoptosis ( Malumbres and Barbacid, 2003 ).”
Background
Exosomal KRAS mutation promotes the formation of tumor-associated neutrophil extracellular traps and causes deterioration of colorectal cancer by inducing IL-8 expression
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An MRAS, SHOC2, and SCRIB Complex Coordinates ERK Pathway Activation with Polarity and Tumorigenic Growth
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“RASproteins (H-, N- and K-RAS) function asmolecular switches, cycling between active GTP-bound and inactive GDP-bound states, and are mutated in 30% of human tumors (Malumbres and Barbacid, 2003).”
Background
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“Among these, the most extensively characterized are the RAF/MEK/ERK and the PI3K/AKT/mTOR signaling pathways (1, 2).”
Background
RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms
Yang, X., & Wu, H. K. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01631-9 · Cited by 133
KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma
Rekhtman, N., Ang, D. C., Riely, G. J., Ladanyi, M., & Moreira, A. L. (2013) · Modern Pathology · doi:10.1038/modpathol.2013.74 · Cited by 117
Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer
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Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers
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The p38 MAPK stress pathway as a tumor suppressor or more?
Loesch, M. (2008) · Frontiers in bioscience · doi:10.2741/2951 · Cited by 115
“Targeting Ras oncogene has been therefore an intensive research for cancer therapeutic development for several decades (27, 28, 33).”
Background
A Germline Mutation (A339V) in Thyroid Transcription Factor-1 (TITF-1/NKX2.1) in Patients With Multinodular Goiter and Papillary Thyroid Carcinoma
Ngan, E., Lang, B. H., Liu, T., Shum, C. K. Y., So, M.-T., Lau, D. K., Leon, T. Y. Y., Cherny, S. S., Tsai, S. Y., Lo, C., et al. (2009) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djn471 · Cited by 115
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K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells
Meter, M. E. M. V., Díaz-Flores, E., Archard, J. A., Passegue, E. A., Irish, J. M., Kotecha, N., Nolan, G. P., Shannon, K., & Braun, B. S. (2006) · Blood · doi:10.1182/blood-2006-09-047530 · Cited by 114
Legionella pneumophilaStrain 130b Possesses a Unique Combination of Type IV Secretion Systems and Novel Dot/Icm Secretion System Effector Proteins
Schroeder, G. N., Petty, N. K., Mousnier, A., Harding, C. R., Vogrin, A. J., Wee, B. A., Fry, N. K., Harrison, T. G., Newton, H. J., Thomson, N. R., et al. (2010) · Journal of Bacteriology · doi:10.1128/jb.00778-10 · Cited by 110
“The Ras subfamily of Ras GTPases is involved in the regulation of a wide variety of cellular processes, such as cell proliferation, adhesion, movement, division, secretion, and differentiation, which makes the members attractive targets for bacterial effector proteins (28, 64).”
Background
Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial
Ocvirk, J. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i25.3133 · Cited by 114
Beyond BRAF: where next for melanoma therapy?
Fedorenko, I. V., Gibney, G. T., Sondak, V. K., & Smalley, K. S. M. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.476 · Cited by 117
“…control a wide array of cellular functions, including growth, survival and invasion, by relaying signals from activated RTKs at the cell surface to downstream effectors in the nucleus, including cell-cycle proteins and transcription factors (Malumbres and Barbacid, 2003; Cully and Downward, 2008).”
Background
HRAS and the Costello syndrome
Rauen, K. (2007) · Clinical Genetics · doi:10.1111/j.1399-0004.2007.00743.x · Cited by 119
“Mouse models have shown that kras is critical for normal mouse development (32), whereas hras and nras are not (33).”
Background
Isoform-Specific Ras Functions in Development and Cancer
Quinlan, M. P., & Settleman, J. E. (2009) · Future Oncology · doi:10.2217/14796694.5.1.105 · Cited by 111
RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells
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“The architecture of the EGFR-RAS-MEKsignaling pathway is evolutionarily ancient and increased in complexity during evolution (Malumbres and Barbacid, 2003; Yarden and Pines, 2012).”
Spatial effects − site-specific regulation of actin and microtubule organization by septin GTPases
Spiliotis, E. T. (2018) · Journal of Cell Science · doi:10.1242/jcs.207555 · Cited by 110
“Actin filament and MT organization is regulated by effectors of the Ras, Rho and Ran families of small GTPases, but additional mechanisms are now thought to maintain the homeostatic balance of different sub-networks and control their size, density and pattern (Heasman and Ridley, 2008; Malumbres and Barbacid, 2003).”
Background
Raf kinases: Oncogenesis and drug discovery
Schreck, R., & Rapp, U. R. (2006) · International Journal of Cancer · doi:10.1002/ijc.22144 · Cited by 110
Genetic Alterations of K-ras, p53, c-erbB-2, and DPC4 in Pancreatic Ductal Adenocarcinoma and Their Correlation With Patient Survival
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Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations
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“KRAS mutations are one of the most frequent alterations in cancer (10, 11), including pancreatic cancer (~70-90%) (12), colorectal cancer (50%) (13), and lung adenocarcinoma (30%) (14).”
Mutationally activated Rho GTPases in cancer
Alan, J. K., & Lundquist, E. A. (2013) · Small GTPases · doi:10.4161/sgtp.26530 · Cited by 110
“This mutation is a well-characterized activating mutation, and is a frequently occurring Ras mutation in various cancer types.(43) There is also emerging evidence that Rho proteins may be mutationally activated in other forms of cancer.”
Background
Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) Controls Activation of Extracellular Signal-Regulated Kinase (ERK) Signaling in the Striatum and Long-Term Behavioral Responses to Cocaine
Fasano, S., D'Antoni, A., Orban, P. C., Valjent, E., Putignano, E., Vara, H., Pizzorusso, T., Giustetto, M., Yoon, B.-J., Soloway, P. D., et al. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.03.014 · Cited by 107
MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice
Cogoi, S., Zorzet, S., Rapozzi, V., Géci, I., Pedersen, E. B., & Xodo, L. E. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt127 · Cited by 106
“It should be remembered that the growth of Panc-1 cells strongly depends on KRAS expression because this gene is mutated in exon 1; thus, it produces a constitutively active p21 protein that stimulates cell growth (37,38).”
Background
KRAS Gene Mutation in Colorectal Cancer Is Correlated With Increased Proliferation and Spontaneous Apoptosis
Liu, X., Jakubowski, M. A., & Hunt, J. L. (2011) · American Journal of Clinical Pathology · doi:10.1309/ajcp7fo2vaxivstp · Cited by 107
An overview of apoptosis and the prevention of colorectal cancer
Watson, A. J. M. (2005) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2005.06.005 · Cited by 108
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“RAS is a member of a large family of approximately 21-kDa membrane-associated monomeric GTPases, which cycles between a GTP-bound active and a GDPbound inactive state [Malumbres and Barbacid, 2003].”
Background
The phosphorylation specificity of B-RAFWT, B-RAFD594V, B-RAFV600E and B-RAFK601E kinases: An in silico study
Fratev, F., & Jónsdóttir, S. Ó. (2009) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2009.12.005 · Cited by 109
Role of Ras/Raf/MEK/ERK signaling in physiological hematopoiesis and leukemia development
Chung, E., & Kondo, M. (2010) · Immunologic Research · doi:10.1007/s12026-010-8187-5 · Cited by 107
Unshackling the links between reovirus oncolysis, Ras signaling, translational control and cancer
Shmulevitz, M., Marcato, P., & Lee, P. W. K. (2005) · Oncogene · doi:10.1038/sj.onc.1209041 · Cited by 108
“Reovirus replication as a method of understanding the role of Ras signaling cascades in cancer Aberrations in Ras proteins have been implicated in cell proliferation, transformation, invasion and metastasis (Malumbres and Barbacid, 2001, 2003).”
Method
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
Analysis of colorectal adenocarcinoma tissue by desorption electrospray ionization mass spectrometric imaging
Gerbig, S., Golf, O., Balog, J., Dénes, J., Baranyai, Z., Zaránd, A., Rásó, E., Tı́már, J., & Takáts, Z. (2012) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-012-5841-x · Cited by 103
Effectors of Epidermal Growth Factor Receptor Pathway: The Genetic Profiling of KRAS, BRAF, PIK3CA, NRAS Mutations in Colorectal Cancer Characteristics and Personalized Medicine
Shen, Y., Wang, J., Han, X., Yang, H., Wang, S., Lin, D., & Shi, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081628 · Cited by 101
“The RAS gene (KRAS, NRAS, HRAS) encodes a series of GTP/GDP related switches that convey extracellular signals, resulting in regulating growth and survival of cells [43].”
Background
The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells
Melillo, R. M., Castellone, M. D., Guarino, V., Falco, V. D., Cirafici, A. M., Salvatore, G., Caiazzo, F., Basolo, F., Giannini, R., Kruhøffer, M., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22758 · Cited by 298
“Once activated, RAF kinases can phosphorylate MEK, which in turn phosphorylates and activates ERKs (11).”
Background
Retracted
Activation of KRAS promotes the mesenchymal features of basal-type breast cancer
Kim, R.-K., Suh, Y., Yoo, K.-C., Cui, Y., Kim, H., Kim, M.-J., Kim, I. G., & Lee, S.-J. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.99 · Cited by 97
Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications
Ferreira, A. I., Pereira, F. D. S., Reis, C. A., Oliveira, M. J., Sousa, M. J., & Preto, A. (2022) · Cells · doi:10.3390/cells11142183 · Cited by 111
“Downstream of this, ERK can regulate numerous transcription factors and cellular functions, such as cell cycle progression, proliferation, autophagy and apoptosis (Figure 1) [16,27].”
Background
Role of First-Line Anti–Epidermal Growth Factor Receptor Therapy Compared With Anti–Vascular Endothelial Growth Factor Therapy in Advanced Colorectal Cancer: A Meta-Analysis of Randomized Clinical Trials
Khattak, M. A., Martin, H. L., Davidson, A., & Phillips, M. R. (2015) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2014.12.011 · Cited by 99
“The rat sarcoma (RAS) proto-oncogenes (HRAS, KRAS, and NRAS) are involved in the transmission of extracellular signals through guanosine diphosphate/guanosine triphosphateeregulated switches to regulate cellular growth and survival.(7) Mutations in the Kirsten rat sarcoma (KRAS) viral oncogene are common in advanced C…”
SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a
Jing, H., Zhang, X., Wisner, S., Chen, X., Spiegelman, N. A., Linder, M. E., & Lin, H. (2017) · eLife · doi:10.7554/elife.32436 · Cited by 102
“They act as binary switches: they are active when GTP is bound, turning on specific signaling pathways by recruiting effector proteins, and inactive in the GDP-bound state (Hancock, 2003; Malumbres and Barbacid, 2003).”
BackgroundInfluential
CagA-mediated pathogenesis of Helicobacter pylori
Tohidpour, A. (2016) · Microbial Pathogenesis · doi:10.1016/j.micpath.2016.01.005 · Cited by 100
A Double-Edged Sword: How Oncogenes and Tumor Suppressor Genes Can Contribute to Chromosomal Instability
Orr, B., & Compton, D. A. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00164 · Cited by 109
“…an array of cancer types and de-regulated signaling through receptor-tyrosine kinase pathways caused by mutant Ras (or its GAP or GEF) affects cell cycle regulation, apoptosis, and cell www.frontiersin.org June 2013 | Volume 3 | Article 164 | 5 survival (reviewed in Malumbres and Barbacid, 2003).”
Background
Novel type of Ras effector interaction established between tumour suppressor NORE1A and Ras switch II
Stieglitz, B., Bee, C., Schwarz, D. F., Yıldız, Ö., Moshnikova, A., Khokhlatchev, A. V., & Herrmann, C. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.125 · Cited by 98
“intracellular signalling that typically leads to cell growth and proliferation (Malumbres and Barbacid, 2003).”
Background
Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: Beyond KRAS mutations
Custodio, A., & Feliú, J. (2012) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2012.05.001 · Cited by 100
“NRAS is a member of the KRAS oncogene family and s mapped on chromosome 1 [106].”
Background
Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity
Winters, I. P., Chiou, S., Paulk, N. K., McFarland, C. D., Lalgudi, P. V., Ma, R. K., Lisowski, L., Connolly, A. J., Petrov, D. A., Kay, M. A., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01519-y · Cited by 94
Mutation status and prognostic values of KRAS, NRAS, BRAF and PIK3CA in 353 Chinese colorectal cancer patients
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Immunological and genetic bases of new primary immunodeficiencies
Maródi, L., & Notarangelo, L. D. (2007) · Nature reviews. Immunology · doi:10.1038/nri2195 · Cited by 95
Therapeutic Silencing of KRAS Using Systemically Delivered siRNAs
Pecot, C. V., Wu, S. Y., Bellister, S. A., Filant, J., Rupaimoole, R., Hisamatsu, T., Bhattacharya, R., Maharaj, A., Azam, S. H., Rodriguez‐Aguayo, C., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0074 · Cited by 96
“Furthermore, the conformational changes following substitution of glycine (only amino acid without a side chain) for other residues in the ‘finger loop’ sterically interferes with GAP activity, making development of GAPmimics unlikely(18).”
Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines
Vitiello, P. P., Cardone, C., Martini, G., Ciardiello, D., Belli, V., Matrone, N., Barra, G., Napolitano, S., Della Corte, C., Turano, M., et al. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1035-0 · Cited by 96
Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway
Drosten, M., Sum, E. Y. M., Lechuga, C. G., Simón-Carrasco, L., Jacob, H. K. C., García-Medina, R., Huang, S., Beijersbergen, R. L., Bernards, R., & Barbacid, M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417549111 · Cited by 103
“GTP-loaded Ras proteins promote activation of various downstream signal transduction pathways, mainly the Raf/Mek/Erk kinase cascade, the PI3K/Akt route, and the Ral guanine dissociation stimulator (RalGDS) pathway (1).”
BackgroundSelf-citation
Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ
Guo, R., Wan, E. C. K., Carpenter, J. H., Mousallem, T. I., Boustany, R., Kuan, C.-T., Burks, A. W., & Zhong, X.-P. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711856105 · Cited by 96
“Constitutive elevation of Ras activity has been detected in many human solid tumors and a subset of T lymphocytic leukemia (42).”
Background
Barriers to horizontal cell transformation by extracellular vesicles containing oncogenic H-ras
Lee, T. H., Chennakrishnaiah, S., Meehan, B., Montermini, L., Garnier, D., D’Asti, E., Hou, W., Magnus, N., Gayden, T., Jabado, N., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.10627 · Cited by 99
“RAS oncogenes exhibit potent transforming effects demonstrated in a wide range of susceptible target cells in vitro and in vivo [24, 25].”
Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis
Yin, C., Zhu, B., Zhang, T., Liu, T., Chen, S., Liu, Y., Li, X., Miao, X., Li, S., Mi, X., et al. (2019) · Cell · doi:10.1016/j.cell.2019.01.002 · Cited by 94
Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches
Ghosh, S., Javia, A., Shetty, S. R., Bardoliwala, D., Maiti, K., Banerjee, S., Khopade, A. J., Misra, A. R., Sawant, K. K., & Bhowmick, S. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.07.014 · Cited by 95
Impeded Nedd4-1-Mediated Ras Degradation Underlies Ras-Driven Tumorigenesis
Zeng, T., Wang, Q., Fu, J., Lin, Q., Bi, J., Ding, W., Qiao, Y., Zhang, S., Zhao, W., Lin, H., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.03.045 · Cited by 92
“…H-Ras, and N-Ras) are small guanosine triphosphatases (GTPases) that act as key molecular switches in regulating a wide range of cellular processes, especially in controlling cell proliferation, transformation, differentiation, and survival (Ahearn et al., 2012; Malumbres and Barbacid, 2003).”
BRAF and KRAS mutations in prostatic adenocarcinoma
Cho, N., Choi, M., Kim, B., Cho, Y., Moon, K. C., & Kang, G. H. (2006) · International Journal of Cancer · doi:10.1002/ijc.22071 · Cited by 94
Somatic NRAS mutation in patient with generalized lymphatic anomaly
Manevitz-Mendelson, E., Leichner, G. S., Barel, O., Avraham‐Davidi, I., Ziv-Strasser, L., Eyal, E., Pessach, I. M., Rimon, U., Barzilai, A., Hirshberg, A., et al. (2018) · Angiogenesis · doi:10.1007/s10456-018-9595-8 · Cited by 93
“[41] for genetic studies in single patients: (1) population studies indicate that the mutation does not occur in healthy individuals; (2) NRAS Q61R is a known oncogenic mutation, occurring in 20% of malignant melanomas, and the mutation increases the activity of NRAS by persistence of the GTP-bound state [42, 43]; (3)…”
Background
Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability
Adhikari, H., & Counter, C. M. (2018) · Nature Communications · doi:10.1038/s41467-018-05692-6 · Cited by 90
Oncogenic G12D mutation alters local conformations and dynamics of K-Ras
Vatansever, S., Erman, B., & Gumus, Z. H. (2019) · Scientific Reports · doi:10.1038/s41598-019-48029-z · Cited by 89
Clinical and molecular aspects of RAS related disorders
Denayer, E., de Ravel, T. J. L., & Legius, E. (2008) · Journal of Medical Genetics · doi:10.1136/jmg.2007.055772 · Cited by 97
“the highest in adenocarcinoma of the pancreas (90%), colon (50%), thyroid (50%), lung (30%), and melanoma (25%).(14) Mutations are found most frequently in KRAS (about 85% of total), less in NRAS (about 15%), and rarely in HRAS (,1%).”
Background
RAS: Target for Cancer Therapy
Saxena, N., Lahiri, S. S., Hambarde, S., & Tripathi, R. P. (2008) · Cancer Investigation · doi:10.1080/07357900802087275 · Cited by 92
“RAS is mutationally activated in 30% of all cancers, with pancreas (90%), colon (50%), thyroid (50%), lung (30%) and melanoma (25%) having the highest prevalence (4).”
Background
K-Ras Promotes Angiogenesis Mediated by Immortalized Human Pancreatic Epithelial Cells through Mitogen-Activated Protein Kinase Signaling Pathways
Matsuo, Y., Campbell, P. M., Brekken, R. A., Sung, B., Ouellette, M. M., Fleming, J. B., Aggarwal, B. B., Der, C. J., & Guha, S. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0577 · Cited by 91
“proteins is seen with such high frequency (90%) in pancreatic ductal adenocarcinoma (5), it is reasonable to consider that clarifying the role of K-Ras in pancreatic cancer carcinogenesis and targeting this signaling pathway is fundamental to improv-”
Background
Decreased Expression of the RAS-GTPase Activating Protein RASAL1 Is Associated With Colorectal Tumor Progression
Ohta, M., Seto, M., Ijichi, H., Miyabayashi, K., Kudo, Y., Mohri, D., Asaoka, Y., Tada, M., Tanaka, Y., Ikenoue, T., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.09.063 · Cited by 90
Identification of Y-Box Binding Protein 1 As a Core Regulator of MEK/ERK Pathway-Dependent Gene Signatures in Colorectal Cancer Cells
Jürchott, K., Kuban, R., Krech, T., Blüthgen, N., Stein, U., Walther, W., Friese, C., Kiełbasa, S. M., Ungethüm, U., Lund, P., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001231 · Cited by 90
“The RTK/RAS pathway triggers multiple properties of cancer cells [12;13].”
Background
Serous and Mucinous Borderline (Low Malignant Potential) Tumors of the Ovary
Ács, G. (2005) · Pathology Patterns Reviews · doi:10.1309/j6pxxk1hqjaebvpm · Cited by 91
New insights into molecular and cellular mechanisms of zoledronate in human osteosarcoma
Lu, K., Lu, E. W.-H., Lin, C., Yang, J., & Yang, S.-F. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107611 · Cited by 90
KRAS G12C inhibitor combination therapies: current evidence and challenge
Miyashita, H., Kato, S., & Hong, D. S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1380584 · Cited by 102
Properties of FDA-approved small molecule protein kinase inhibitors: A 2025 update
Roskoski, R. J. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107723 · Cited by 104
Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/MKP2) resulting in nuclear ERK1/2 inhibition
Cagnol, S., & Rivard, N. (2012) · Oncogene · doi:10.1038/onc.2012.88 · Cited by 93
Knock-in of Mutant K- ras in Nontumorigenic Human Epithelial Cells as a New Model for Studying K- ras –Mediated Transformation
Konishi, H., Karakas, B., Abukhdeir, A. M., Lauring, J. D., Gustin, J. P., Garay, J. P., Konishi, Y., Gallmeier, E., Bachman, K. E., & Park, B. H. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0108 · Cited by 90
“receptor can also result in MAPK and PI3K signaling serving as an internal positive control for each cell line (2).”
BackgroundInfluential
Kirsten Ras* oncogene: Significance of its discovery in human cancer research
Tsuchida, N., Murugan, A. K., & Grieco, M. (2016) · Oncotarget · doi:10.18632/oncotarget.8773 · Cited by 94
Canonical RTK-Ras-ERK signaling and related alternative pathways
Sundaram, M. V. (2013) · WormBook · doi:10.1895/wormbook.1.80.2 · Cited by 86
“GEFs and GAPs: As is the case for other small GTPases, the activity of LET-60/Ras is controlled by Guanine Nucleotide Exchange Factors (GEFs), which activate Ras by stimulating conversion of Ras-GDP to Ras-GTP, and by GTPase activating proteins (GAPs), which inactivate Ras by stimulating conversion of Ras-GTP to Ras-G…”
BackgroundInfluential
KRAS Mutation Testing in Human Cancers: The Pathologist's Role in the Era of Personalized Medicine
Wang, H. L., Lopategui, J. R., Amin, M. B., & Patterson, S. D. (2010) · Advances in Anatomic Pathology · doi:10.1097/pap.0b013e3181c6962f · Cited by 90
“The gene KRAS encodes KRAS, a member of the Ras family of small guanine nucleotide–binding proteins first identified as a cellular homolog of a transforming gene in the Kirsten rat sarcoma virus.(39,41) KRAS is a key component of intracellular signaling pathways regulated by a broad variety of cell surface receptors,…”
Background
Targeted therapy for lung cancer: Beyond EGFR and ALK
Herrera, M., Serrano‐Gómez, C., Bote, H., & Paz-Ares, L. G. (2023) · Cancer · doi:10.1002/cncr.34757 · Cited by 94
“1 that plays a crucial role in cell division, tumor initiation, progression, and drug resistance.(62) RAS proteins are characterized by intrinsic GTPase activity, which is enhanced by a family of regulatory proteins known as GTPase activator proteins.”
Background
Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells
Santoriello, C., Deflorian, G., Pezzimenti, F., Kawakami, K., Lanfrancone, L., di Fagagna, F. D., & Mione, M. (2008) · Disease Models & Mechanisms · doi:10.1242/dmm.001016 · Cited by 88
“They have been intensely studied in the last 30 years for their involvement in cancer; indeed, defects in Ras signaling may result in malignant transformation (Downward, 1996; Malumbres and Barbacid, 2003).”
A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors
Rosen, L. S., LoRusso, P. M., Ma, W. W., Goldman, J. W., Weise, A. M., Colevas, A. D., Adjei, A. A., Yazji, S., Shen, A., Johnston, S. H., et al. (2016) · Investigational New Drugs · doi:10.1007/s10637-016-0374-3 · Cited by 91
The Ras switch in structural and historical perspective
Gasper, R., & Wittinghofer, F. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0330 · Cited by 92
“The first effector to be identified by several groups in 1993 (see reviews by Malumbres and Barbacid, 2003; Cox and Der, 2010) was the protein kinase c-Raf which had already previously been assumed to be involved in the Ras pathway.”
Background
LEOPARD Syndrome: Clinical Features and Gene Mutations
Martínez‐Quintana, E., & Rodríguez-González, F. (2012) · Molecular Syndromology · doi:10.1159/000342251 · Cited by 85
“RAS protein family members belong to a class of proteins called small GTPases, and are involved in transmitting signals within cells [Malumbres and Barbacid, 2003].”
Background
A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth
Fernández-Zapico, M. E., Lomberk, G. A., Tsuji, S., DeMars, C. J., Bardsley, M. R., Lin, Y., Almada, L. L., Han, J.-J., Mukhopadhyay, D., Ördög, T., et al. (2011) · Biochemical Journal · doi:10.1042/bj20100773 · Cited by 86
Prognostic significance of alterations in KRAS isoforms KRAS‐4A/4B and KRAS mutations in colorectal carcinoma
Abubaker, J. A., Bavi, P. P., Al‐Haqawi, W., Sultana, M., Al-harbi, S., Al-Sanea, N. A., Abduljabbar, A. S., Ashari, L. H. S., Alhomoud, S. J., Al‐Dayel, F., et al. (2009) · The Journal of Pathology · doi:10.1002/path.2625 · Cited by 86
“The three classical mammalian ras genes, K -, N -, and H-ras, encode 21 kD proteins that are members of the guanine nucleotide binding protein superfamily [4].”
Background
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
“RAS signaling is critical for the proliferation and migration of normal cells.(23) To investigate whether RASON modulates RAS signaling in vivo, we generated Rason homologues KO mice by deletion of the entire sORF (Supplementary information, Fig.”
Method
DLC1: a significant GAP in the cancer genomePreprint
Lahoz, A., & Hall, A. (2008) · Genes & Development · doi:10.1101/gad.1691408 · Cited by 86

Authors: Malumbres, M., & Barbacid, M.
Affiliations: Spanish National Cancer Research Centre (ES)
Corresponding author: Malumbres, Marcos
Barbacid, Mariano
ORCID: Malumbres, Marcos
Barbacid, Mariano
Venue: Nature Reviews Cancer
Publisher: Springer Science and Business Media LLC
Published: 2003-06-01
Volume: 3
Issue: 6
Pages: 459-465
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc1097
OpenAlex: W2083695927
Cited by: 1,902
References: 122
Citations by year: 2026: 39 · 2025: 77 · 2024: 94 · 2023: 84 · 2022: 89 · 2021: 78 · 2020: 68 · 2019: 74 · 2018: 80 · 2017: 99 · 2016: 91 · 2015: 98 · 2014: 117 · 2013: 120 · 2012: 104
FWCI: 3.49
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
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 › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords: oncogenic Ras, signal transduction, molecular oncology, RAS inhibitors, cancer therapy
MeSH terms: Animals, Humans, Genes, ras, Biomedical Research, History, 20th Century, History, 21st Century

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RAS oncogenes: the first 30 years

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