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KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures
Abstract
Cancers of nearly all lineages harbor alterations that deregulate mitogen-activated protein kinase signaling, a crucial signaling pathway for tumor formation and maintenance. Of these, KRAS mutations are the most frequent gain-of-function alterations found in patients with cancer. In particular they represents the most common molecular alteration detected in non-small cell lung cancer (NSCLC) accounting for up to 25% of all oncogenic mutations. They were identified decades ago and prior efforts to target these proteins have been unsuccessful. KRAS mutation profiles (i.e. frequency of specific codon substitutions) in smokers and never-smokers are distinct and not all KRAS alterations are driver mutations. KRAS has evolved from a mutation with possible predictive value to a therapeutic target with great promise. Here, we will discuss the biology of KRAS in lung cancer and its clinical implications in oncology today and in the foreseeable future.
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“G12C and G12V mutations are shown to preferentially activate RAL signaling and G12D-mutant cell lines are shown to have high levels of phosphorylated AKT, suggesting preferential activation of PI3K-AKT-mTOR pathway [46, 47].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [47]
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Metadata
- Authors
- Friedlaender, A., Drilon, A., Weiss, G. J., Banna, G. L., & Addeo, A.
- Affiliations
- University Hospital of Geneva (CH)
- Memorial Sloan Kettering Cancer Center (US)
- United Lincolnshire Hospitals NHS Trust (GB)
- Corresponding author
- Addeo, Alfredo
- Venue
- Cancer Treatment Reviews
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 85
- Pages
- 101978
- ISSN
- 0305-7372 (ISSN-L)
- OpenAlex
- W3004931546
- Cited by
- 118
- References
- 52
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 17 · 2023: 20 · 2022: 24 · 2021: 22 · 2020: 19
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Treatment Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS mutation, non-small cell lung cancer, druggable targets, MAPK signaling, gain-of-function mutations, smoking status, driver mutations, KRAS inhibitors, cancer therapeutics
- MeSH terms
- Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Forecasting, Humans, Immunotherapy, Lung Neoplasms, Male, Mutation, Gene Expression Regulation, Neoplastic, Survival Analysis, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Molecular Targeted Therapy
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