KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures

Friedlaender, Alex; Drilon, Alexander; Weiss, Glen J.; Banna, Giuseppe L.; Addeo, Alfredo

doi:10.1016/j.ctrv.2020.101978

Cited by 118Lung Cancer Treatments and MutationsProtein Kinase Regulation and GTPase SignalingCancer Genomics and Diagnostics

KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures

Friedlaender, Alex, Drilon, Alexander, Weiss, Glen J., Banna, Giuseppe L., Addeo, Alfredo·2020·Cancer Treatment Reviews

DOI 10.1016/j.ctrv.2020.101978

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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 preferentially activate RAL signaling and G12D-mutant cell lines have high levels of phosphorylated AKT, suggesting preferential activation of PI3K-AKT-mTOR pathway.
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From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [47]

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KRAS Mutations in Squamous Cell Carcinomas of the Lung
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The discovery of novel imidazo[1,2- a ]pyridine derivatives as covalent anticancer agents
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Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC
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Vertebral Metastasis Treated by Vertebroplasty, a Cause of Respiratory Failure: Case Report and Literature Review
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Biomarkers for Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer
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KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target
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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
ORCID: Friedlaender, Alex
Drilon, Alexander
Weiss, Glen J.
Banna, Giuseppe L.
Addeo, Alfredo
Venue: Cancer Treatment Reviews
Publisher: Elsevier BV
Published: 2020-04
Volume: 85
Pages: 101978
ISSN: 0305-7372 (ISSN-L)
DOI: 10.1016/j.ctrv.2020.101978
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures

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