ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of KRAS Mutations in Non-Small Cell Lung Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 38 citations in OpenAlex.
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- Therapeutic inhibition of RAS in non-small cell lung cancer.Frontiers in oncology · 2026Review
- Shaping the battlefield: EGFR and KRAS tumor mutations' role on the immune microenvironment and immunotherapy responses in lung cancer.Cancer metastasis reviews · 2025Review
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- RASON promotes KRASJournal of experimental & clinical cancer research : CR · 2025Article
- SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRASProceedings of the National Academy of Sciences of the United States of America · 2025Article
- MicroRNAs and lung cancer: overview of essential pathways and somatic mutations in cancer progression.Frontiers in oncology · 2025Review
- The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASMolecular cancer · 2024Article
- Additional impact of genetic ancestry over race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer.HGG advances · 2024Article
- Spatial iTME analysis of KRAS mutant NSCLC and immunotherapy outcome.NPJ precision oncology · 2024Article
- Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2024Article
- A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Mesenchymal Stem Cell-Derived Extracellular Vesicles in Cancer Therapy Resistance: from Biology to Clinical Opportunity.International journal of biological sciences · 2024Review
- Phase II Study of Docetaxel and Trametinib in Patients with KRAS Mutation Positive Recurrent Non-Small Cell Lung Cancer (NSCLC; SWOG S1507, NCT-02642042).Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Divide and conquer: towards isoform-specific diagnosis and therapy ofTranslational lung cancer research · 2023Article
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26 authors at 6 institutions in 4 countries.
Funding
Abstract
purposeActivating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking. EXPERIMENTAL
designWe developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non-small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations.
resultsIn isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors.
conclusionsThis study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.
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