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RAS oncogenes: the first 30 years
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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“On the other hand, the KRAS proteins are featureless. They have a nearly spherical structure that lacks a deep hydrophobic pocket and has no obvious binding site [20].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [20]
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RAS Is Regulated by the let-7 MicroRNA Family
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KRAS-Mutant non-small cell lung cancer: From biology to therapy
Ferrer, I., Zugazagoitia, J., Herbertz, S., John, W. J., Paz-Ares, L. G., & Schmid‐Bindert, G. (2018) · Lung Cancer · doi:10.1016/j.lungcan.2018.07.013 · Cited by 315
Genetic Alterations in the Phosphatidylinositol-3 Kinase/Akt Pathway in Thyroid Cancer
Xing, M. (2010) · Thyroid · doi:10.1089/thy.2010.1646 · Cited by 309
“Mutations in the three types of Ras genes—H-Ras, K-Ras, and N-Ras—are commonly seen in human cancers with a frequency, on average, of 30% (34,35).”
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. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87345 · Cited by 305
RetractedKRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target
Román, M., Baraibar, I., López, I., Nadal, E., Rolfo, C., Vicent, S., & Gil-Bazo, I. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0789-x · Cited by 301
“During the following two decades, studies of RAS focused on its biology and biochemical characteristics both in normal and cancer cells, as well as in the signaling cascade in which RAS is involved [32].”
BackgroundRas-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway
Nan, X., Tamgüney, T. M., Collisson, E. A., Lin, L.-J., Pitt, C., Galeas, J., Lewis, S., Gray, J. W., McCormick, F., & Chu, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509123112 · Cited by 273
Blasco, R. B., Francoz, S., Santamaría, D., Cañamero, M., Dubus, P., Charron, J., Baccarini, M., & Barbacid, M. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.002 · Cited by 302
“These proteins have been extensively characterized at the structural, biochemical, and cellular level due to their central role in eukaryotic biology, as well as their implication in cancer development (Malumbres and Barbacid, 2003; Karnoub and Weinberg, 2008).”
InfluentialVandevyver, S., Dejager, L., Tuckermann, J., & Libert, C. (2013) · Endocrinology · doi:10.1210/en.2012-2045 · Cited by 296
Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos
Zhao, C., Du, G., Skowronek, K., Frohman, M. A., & Bar‐Sagi, D. (2007) · Nature Cell Biology · doi:10.1038/ncb1594 · Cited by 306
Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer
Janakiraman, M., Vakiani, E., Zeng, Z., Pratilas, C. A., Taylor, B. S., Chitale, D., Halilovic, E., Wilson, M., Huberman, K., Ricarte Filho, J. C., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0192 · Cited by 290
“Constitutive mitogen-activated protein kinase (MAPK) activation is frequent in human cancer and is often the result of activating mutations in RAS (1, 2).”
BackgroundOncogenic Ras in tumour progression and metastasis
Giehl, K. (2005) · Biological Chemistry · doi:10.1515/bc.2005.025 · Cited by 292
Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer
Bruntz, R. C., Lindsley, C. W., & Brown, H. A. (2014) · Pharmacological Reviews · doi:10.1124/pr.114.009217 · Cited by 286
“Ras was one of the earliest identified oncogenes, first discovered as a viral protein capable of inducing sarcoma in rats (Malumbres and Barbacid, 2003).”
BackgroundSignalling scaffolds and local organization of cellular behaviour
Langeberg, L. K., & Scott, J. D. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3966 · Cited by 284
Multivalent Small-Molecule Pan-RAS Inhibitors
Welsch, M., Kaplan, A. R., Chambers, J. M., Stokes, M. E., Bos, P. H., Zask, A., Zhang, Y., Sánchez-Martín, M., Badgley, M. A., Huang, C., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.006 · Cited by 282
“, I36–S39), or of the interacting residues on the primary effector proteins (RAF, PI3K, or RALGDS), has been reported to lower binding affinity for effector proteins to RAS proteins (Colicelli, 2004; Gysin et al., 2011; Hall et al., 2002; Huang et al., 1998; Huang et al., 1997; Karnoub and Weinberg, 2008; Malumbres an…”
Unravelling the tumor-suppressive functions of FOXO proteins
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ERK1/2 Phosphorylate Raptor to Promote Ras-dependent Activation of mTOR Complex 1 (mTORC1)
Carriere, A., Romeo, Y., Acosta-Jaquez, H. A., Moreau, J., Bonneil, E., Thibault, P., Fingar, D. C., & Roux, P. P. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159046 · Cited by 268
The Multifaceted Role of MTDH/AEG-1 in Cancer Progression
Hu, G., Wei, Y., & Kang, Y. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0049 · Cited by 267
Aberrant Signaling Pathways in Glioma
Nakada, M., Kita, D., Watanabe, T., Hayashi, Y., Teng, L., Pyko, I. V., & Hamada, J. (2011) · Cancers · doi:10.3390/cancers3033242 · Cited by 277
“The RAS gene family comprises four different genes that encode HRAS, NRAS, KRAS4A, and KRAS4B [149,150].”
BackgroundChemical remodeling of a cellular chaperone to target the active state of mutant KRAS
Schulze, C. J., Seamon, K. J., Zhao, Y., Yang, Y. C., Cregg, J., Kim, D., Tomlinson, A., Choy, T. J., Wang, Z., Sang, B., et al. (2023) · Science · doi:10.1126/science.adg9652 · Cited by 264
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
NRAS mutation causes a human autoimmune lymphoproliferative syndrome
Oliveira, J. B., Bidère, N., Niemela, J. E., Zheng, L., Sakai, K., Nix, C. P., Danner, R. L., Barb, J. J., Munson, P. J., Puck, J. M., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702975104 · Cited by 261
The KRAS oncogene: Past, present, and future
Kranenburg, O. (2005) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2005.10.001 · Cited by 252
Zinc as an anti-tumor agent in prostate cancer and in other cancers
FRANKLIN, R. B., & Costello, L. C. (2007) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2007.02.033 · Cited by 247
Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer
Arrington, A. K., Heinrich, E. L., Lee, W., Duldulao, M., Patel, S., Sanchez, J., Garcia-Aguilar, J., & Kim, J. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131012153 · Cited by 244
“(NIH) [10].”
Ras trafficking, localization and compartmentalized signalling
Prior, I. A., & Hancock, J. F. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.09.002 · Cited by 242
“Over 20 Ras effectors have been identified although most work has focussed on the Raf protein kinase family (A-Raf, B-Raf and c-Raf-1) and the PtdIns-3 kinase (PI3K) family members that regulate cell proliferation and survival respectively (Figure 1; [7, 8]).”
BackgroundProtein tyrosine phosphatase SHP-2: A proto-oncogene product that promotes Ras activation
Matozaki, T., Murata, Y., Saito, Y., Okazawa, H., & Ohnishi, H. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01257.x · Cited by 240
Wu, X., Simpson, J. A., Hong, J. H., Kim, K.-H., Thavarajah, N. K., Backx, P. H., Neel, B. G., & Araki, T. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44929 · Cited by 238
Metadata
- Authors
- Malumbres, M., & Barbacid, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Malumbres, Marcos
- Barbacid, Mariano
- Venue
- Nature Reviews Cancer
- Published
- 2003-06-01
- Volume
- 3
- Issue
- 6
- Pages
- 459-465
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- 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
- 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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