Dragging ras back in the ring

Stephen, Andrew G.; Esposito, Dominic; Bagni, Rachel K.; McCormick, Frank

doi:10.1016/j.ccr.2014.02.017

Cited by 801Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

Dragging ras back in the ring

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Stephen, Andrew G., Esposito, Dominic, Bagni, Rachel K., McCormick, Frank·2014·Cancer Cell

DOI 10.1016/j.ccr.2014.02.017

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Abstract

Ras proteins play a major role in human cancers but have not yielded to therapeutic attack. Ras-driven cancers are among the most difficult to treat and often excluded from therapies. The Ras proteins have been termed "undruggable," based on failures from an era in which understanding of signaling transduction, feedback loops, redundancy, tumor heterogeneity, and Ras' oncogenic role was poor. Structures of Ras oncoproteins bound to their effectors or regulators are unsolved, and it is unknown precisely how Ras proteins activate their downstream targets. These knowledge gaps have impaired development of therapeutic strategies. A better understanding of Ras biology and biochemistry, coupled with new ways of targeting undruggable proteins, is likely to lead to new ways of defeating Ras-driven cancers.

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Clinical trials involving inhibitors against RAF and MEK have not received approval for treating KRAS-mutant cancers.
“Clinical trials involving inhibitors against RAF and MEK have not received approval for treating KRAS-mutant cancers [46].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [46]
Clinically active, covalent KRASG12C inhibitors have provided the first opportunity to directly target this key oncoprotein.
“Clinically active, covalent KRASG12C inhibitors have provided the first opportunity to directly target this key oncoprotein (Canon et al., 2019; Hallin et al., 2020; Stephen et al., 2014).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Stephen et al., 2014
The basis for the specific frequencies of KRAS G12X mutations is poorly understood, and the effects of these specific mutations on a molecular scale are not clear.
“Although frequently observed in cancer, not only is the basis for the specific frequencies of KRAS G12X mutations poorly understood [47], but also the effects of these specific mutations on a molecular scale are not clear.”
From Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling (2018) · cites this paper as [47]

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SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
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The Ras-Erk-ETS-signaling pathway is a drug target for longevity
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ssGSEA score-based Ras dependency indexes derived from gene expression data reveal potential Ras addiction mechanisms with possible clinical implications
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Oncogenic and RASopathy-associated K-RAS mutations relieve membrane-dependent occlusion of the effector-binding site
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Metabolic Dependencies in RAS -Driven Cancers
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Extracellular Vesicles and Their Roles in Cancer Progression
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Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules
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GTP-Dependent K-Ras Dimerization
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Uses and abuses of macropinocytosis
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Survival of pancreatic cancer cells lacking KRAS function
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KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer
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Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles
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Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS -Mutant Lung Cancer
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Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications
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Inhibition of Ras Signaling by Blocking Ras–Effector Interactions with Cyclic Peptides
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The Conundrum of Genetic “Drivers” in Benign Conditions
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Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer’s disease
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Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy
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Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration
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Authors: Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F.
Affiliations: Frederick National Laboratory for Cancer Research (US)
University of California, San Francisco (US)
Corresponding author: McCormick, Frank
ORCID: Stephen, Andrew G.
Esposito, Dominic
McCormick, Frank
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2014-03
Volume: 25
Issue: 3
Pages: 272-281
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2014.02.017
OpenAlex: W2022920832
Cited by: 795
References: 87
Citations by year: 2026: 25 · 2025: 34 · 2024: 44 · 2023: 36 · 2022: 59 · 2021: 63 · 2020: 67 · 2019: 84 · 2018: 95 · 2017: 94 · 2016: 82 · 2015: 80 · 2014: 31
FWCI: 8.85
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 404 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Funders: Frederick National Laboratory for Cancer Research
National Institutes of Health
University of California, San Francisco
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: Ras proteins, RAS-driven cancers, undruggable proteins, Ras signaling, Ras effectors, RAS inhibitors, cancer therapy
MeSH terms: Animals, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Neoplasms, Protein Processing, Post-Translational, Retroviridae Infections, Tumor Virus Infections, Signal Transduction, Oncogene Protein p21(ras), Proto-Oncogene Proteins p21(ras), Mice

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