The genetics and biology of KRAS in lung cancer
Open accessAbstract
Mutational activation of KRAS is a common oncogenic event in lung cancer and other epithelial cancer types. Efforts to develop therapies that counteract the oncogenic effects of mutant KRAS have been largely unsuccessful, and cancers driven by mutant KRAS remain among the most refractory to available treatments. Studies undertaken over the past decades have produced a wealth of information regarding the clinical relevance of KRAS mutations in lung cancer. Mutant Kras-driven mouse models of cancer, together with cellular and molecular studies, have provided a deeper appreciation for the complex functions of KRAS in tumorigenesis. However, a much more thorough understanding of these complexities is needed before clinically effective therapies targeting mutant KRAS-driven cancers can be achieved.
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The difficulty of drugging KRAS reflects picomolar RAS affinity for GTP, high intracellular GTP concentration of about 500 nM, and the absence of a deep or pharmacologically actionable small-molecule-binding pocket; GTP-competitive RAS inhibitors are therefore unfeasible.
“The several-decade struggle to drug KRAS and other RAS isoforms25,61 reflects challenges posed by three key biochemical features: first, the picomolar affinity of RAS proteins for GTP62; second, the high intracellular concentrations of GTP (~500 nM)9; and third, the absence of a deep or pharmacologically actionable small-molecule-binding pocket in the RAS proteins.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [61]
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- Authors
- Westcott, P. M. K., & To, M. D.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Chinese Journal of Cancer
- Published
- 2013-02-05
- Volume
- 32
- Issue
- 2
- Pages
- 63-70
- ISSN
- 1000-467X (ISSN-L)
- 1944-446X
- PMC
- PMC3845615
- OpenAlex
- W1976566249
- Cited by
- 116
- References
- 78
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 8 · 2023: 9 · 2022: 14 · 2021: 15 · 2020: 14 · 2019: 8 · 2018: 8 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 2 · 2013: 1
- FWCI
- 0.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- 癌症:英文版 (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences (T32GM007175)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- KRAS mutation, lung cancer, oncogenic KRAS, carcinogenesis, KRAS-targeted therapy, epithelial cancers, cancer genetics
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, Disease Susceptibility, Humans, Lung Neoplasms, Mutation, Neoplasms, Experimental, Proto-Oncogene Proteins, Genetic Therapy, Signal Transduction, Proto-Oncogene Proteins p21(ras), ras Proteins, RNA, Small Interfering, Mice, Gene Knockdown Techniques
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