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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BackgroundInfluential
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Clinical performance evaluation of the Idylla NRAS-BRAF mutation test on retrospectively collected formalin-fixed paraffin-embedded colorectal cancer tissue
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A New Strategy to Control and Eradicate “Undruggable” Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology
Sciver, R. E. V., Lee, M., Lee, C. G. L., Lafever, A., Svyatova, E. A., Kanda, K., Collier, A. L., van Reesema, L. L. S., Tang-Tan, A. M., Zheleva, V. P., et al. (2018) · Cancers · doi:10.3390/cancers10050142 · Cited by 21
“Controlling and eradicating chemo-resistant, relapsed, and metastatic pancreatic cancer remains a major intellectual challenge and a pressing unmet need in science and medicine [79,82].”
Background
The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients
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“Genetic abnormalities in these pathway genes have been well studied and characterized: APC and CTNNB1 (b-catenin gene) mutations in the Wnt/b-catenin pathway, and KRAS, B-RAF, and EGFR (epidermal growth factor receptor) mutations in the RAS-ERK pathway [28,29].”
Background
Dissecting the Involvement of Ras GTPases in Kidney Fibrosis
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“H-Ras, N-Ras, and K-Ras control and regulate biological functions such as proliferation, differentiation, motility, adhesion, senescence/cell cycle arrest, survival and apoptosis [21].”
Background
Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments
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Computational characterization of the chemical step in the GTP hydrolysis by Ras-GAP for the wild-type and G13V mutated Ras
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Dictyostelium discoideum Nucleoside Diphosphate Kinase C Plays a Negative Regulatory Role in Phagocytosis, Macropinocytosis and Exocytosis
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Molecular Mechanisms of Colorectal Carcinogenesis
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“EGFR is affected by somatic mutations (e.g., point mutations or gene amplifi cation) in fewer than 5 % of CRCs.”
Background
NRAS Mutant Melanoma: An Overview for the Clinician for Melanoma Management
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RAS and Hedgehog - partners in crime
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Chromosomal abnormalities and molecular landscape of metastasizing mucinous salivary adenocarcinoma
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“These mutations activate the PI3K/Akt and Erk1/2 pathways that confer proliferative and survival advantages to cancer cells [28].”
Background
Downregulation of RASAL2 promotes the proliferation, epithelial-mesenchymal transition and metastasis of colorectal cancer cells
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“Aberrant activation of the Ras signaling pathway is common in the majority of human cancers, and is due to mutations in RAS genes, upstream inducers and downstream effectors (8,9).”
Background
Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets
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“RAS proto-oncogenes are among the most frequently mutated in cancer, with ~30% of human and rodent tumors carrying RAS lesions (1).”
Oncogenic N-Ras and Tet2 haploinsufficiency collaborate to dysregulate hematopoietic stem and progenitor cells
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“Activating RAS mutations are prevalent in human cancers, including hematologic malignancies.(23,24) In CMML, oncogenic NRAS and KRAS mutations are found in ;15% to 40% of patients(4,25,26) and are associated with a more proliferative phenotype.”
Background
NRAS and KRAS polymorphisms are not associated with hepatoblastoma susceptibility in Chinese children
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“[7,17-19] In colorectal carcinomas, KRAS mutation has been reported within a broad range of 30 to 50%.[13,17,20,21] This broad range of reported frequencies of KRAS mutations could be due to various factors such as the sensitivity and specificity of mutation detection techniques, patient sample size, variability in an…”
Background
Propiconazole-enhanced hepatic cell proliferation is associated with dysregulation of the cholesterol biosynthesis pathway leading to activation of Erk1/2 through Ras farnesylation
Murphy, L. A., Moore, T., & Nesnow, S. (2012) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2012.02.003 · Cited by 22
“Inhibition of Ras farnesylation as a means to disrupt cell signaling has been a central focus of cancer therapeutic development as it is estimated that 20% of human cancers possess activating Ras mutations (Rao, 1995; Brunner et al., 2003; Malumbres and Barbacid, 2003).”
Background
The Effect of Antineoplastons A10 and AS2-1 and Metabolites of Sodium Phenylbutyrate on Gene Expression in Glioblastoma Multiforme
Burzynski, S. R., & Patil, S. (2014) · Journal of Cancer Therapy · doi:10.4236/jct.2014.510099 · Cited by 20
“From MAPK the signal enters the nucleus where it triggers cell cycle progression from G1 to S phase and proliferation [29].”
Background
Searching for the Chokehold of NRAS Mutant Melanoma
Posch, C., Vujic, I., Monshi, B., Sanlorenzo, M., Weihsengruber, F., Rappersberger, K., & Ortiz-Urda, S. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.03.006 · Cited by 19
“The four highly homologous members of the RAS protein family neuroblastoma-, Harvey-, and KirstenRAS (NRAS, HRAS, KRAS4A, KRAS4B) are ubiquitously expressed and control cellular proliferation, differentiation, and survival (Cox et al., 2014; Malumbres and Barbacid, 2003).”
Background
Oncolytic Virotherapy: The Cancer Cell Side
Ehrlich, M., & Bacharach, E. (2021) · Cancers · doi:10.3390/cancers13050939 · Cited by 23
Oncogenic Landscape of Somatic Mutations Perturbing Pan-Cancer lncRNA-ceRNA Regulation
Zhang, Y., Han, P., Guo, Q., Hao, Y., Qi, Y., Xin, M., Zhang, Y., Cui, B., & Wang, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.658346 · Cited by 20
“, 2019), Ras signaling pathway (Malumbres and Barbacid, 2003), Toll-like receptor (TLR) signaling pathway (Moradi-Marjaneh et al.”
Background
Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited antitumor activity
Sacco, A., Federico, C., Todoerti, K., Ziccheddu, B., Palermo, V., Giacomini, A., Ravelli, C., Maccarinelli, F., Bianchi, G., Belotti, A., et al. (2021) · Blood · doi:10.1182/blood.2020010572 · Cited by 20
Hydrophobic Tagging-Induced Degradation of PDEδ in Colon Cancer Cells
Guo, M., He, S., Cheng, J., Li, Y., Dong, G., & Sheng, C. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00670 · Cited by 21
KRAS and MET in non-small-cell lung cancer: two of the new kids on the ‘drivers’ block
García-Robledo, J. E., Rosell, R., Ruíz-Patiño, A., Sotelo, C., Arrieta, O. G., Zatarain-Barrón, L., Ordóñez‐Reyes, C., Jaller, E., Rojas, L., Russo, A., et al. (2022) · Therapeutic Advances in Respiratory Disease · doi:10.1177/17534666211066064 · Cited by 22
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 20
Identification of KRASG12C Mutations in Circulating Tumor DNA in Patients With Cancer
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“Kirsten RAS (KRAS), one of three RAS isoforms, is the most commonly mutated protooncogene that has been identified in cancer.(1,2,6) Despite its frequency and decades of research, the treatment of patients with KRASmutations still remains an arduous challenge.”
Background
Reverse vaccinology and immunoinformatics approaches to design multi-epitope based vaccine against oncogenic KRAS
Ramalingam, P. S., & Arumugam, S. (2023) · Medical Oncology · doi:10.1007/s12032-023-02160-0 · Cited by 19
Oncogenic KRAS mutation confers chemoresistance by upregulating SIRT1 in non-small cell lung cancer
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Growth and Tumor Suppressor NORE1A Is a Regulatory Node between Ras Signaling and Microtubule Nucleation
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Mitogen-activated protein kinase pathway in osteosarcoma
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“Point mutations in the RAS gene at codons 12, 13, and 61 have been observed in various human neoplasias.(5) The RAF gene family consists of A-RAF, B-RAF and RAF-1.”
Background
Lead acetate induces EGFR activation upstream of SFK and PKCα linkage to the Ras/Raf-1/ERK signaling
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A High-Throughput Assay for Small Molecule Destabilizers of the KRAS Oncoprotein
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“Consequently, the mutant Ras protein is stuck in its GTP-bound state and constitutively signals to its downstream targets, and drives aberrant cell proliferation and survival [2,4].”

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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