ArticleJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2023
Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228.
Article in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 34 citations in OpenAlex.
- Review
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- TheCancer management and research · 2026Review
- Effects of the Pharmacological Modulation of NRF2 in Cancer Progression.Medicina (Kaunas, Lithuania) · 2025Review
- Site-specific prevalence of the NFE2L2 mutation in esophageal squamous cell carcinoma.International journal of clinical oncology · 2025Article
- Refining treatment strategies for non-small cell lung cancer lacking actionable mutations: insights from multi-omics studies.British journal of cancer · 2025Review
- AI cancer driver mutation predictions are valid in real-world data.Nature communications · 2025Article
- Multi-context modeling of driver pathways reveals common and specific mechanisms across 23 cancer types.PLoS computational biology · 2025Article
- Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models.British journal of cancer · 2025Article
- Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2 and Therapeutic Strategies.Cancers · 2025Review
- Decoding the NRF2-NOTCH Crosstalk in Lung Cancer-An Update.Antioxidants (Basel, Switzerland) · 2025Review
- Abnormal changes in metabolites caused by mJournal of advanced research · 2025Review
- NFκB1: a common biomarker linking Alzheimer's and Parkinson's disease pathology.Frontiers in neuroscience · 2025Article
- Targeted therapy combinations with ipatasertib in multi-cell type 3D tumor spheroid models.Academia oncology · 2025Article
- DataXflow: Synergizing data-driven modeling with best parameter fit and optimal control - An efficient data analysis for cancer research.Computational and structural biotechnology journal · 2024Article
- Lessons learned from 20 years of preclinical testing in pediatric cancers.Pharmacology & therapeutics · 2024Review
- Differential impact of intratumor heterogeneity (ITH) on survival outcomes in early-stage lung squamous and adenocarcinoma based on tumor mutational burden (TMB).Translational lung cancer research · 2024Article
- Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities.Trends in pharmacological sciences · 2024Review
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
introductionIncreased insight into the mutational landscape of squamous cell lung cancers (LUSCs) in the past decade has not translated into effective targeted therapies for patients with this disease. NRF2, encoded by NFE2L2, and its upstream regulator, KEAP1, control key aspects of redox balance and are frequently mutated in NSCLCs.
methodsHere, we describe the specific potent activity of TAK-228, a TORC1/2 inhibitor, in NSCLC models harboring NRF2-activating alterations and results of a phase 2 clinical trial of TAK-228 in patients with advanced NSCLC harboring NRF2-activating alterations including three cohorts (NFE2L2-mutated LUSC, KEAP1-mutated LUSC, KRAS/NFE2L2- or KEAP1-mutated NSCLC).
resultsTAK-228 was most efficacious in a LUSC cohort with NFE2L2 alterations; the overall response rate was 25% and median progression-free survival was 8.9 months. Additional data suggest that concurrent inhibition of glutaminase with the glutaminase inhibitor CB-839 might overcome metabolic resistance to therapy in these patients.
conclusionsTAK-228 has single-agent activity in patients with NRF2-activated LUSC. This study reframes oncogenic alterations as biologically relevant based on their downstream effects on metabolism. This trial represents, to the best of our knowledge, the first successful attempt at metabolically targeting NSCLC and identifies a promising targeted therapy for patients with LUSC, who are bereft of genotype-directed therapies.
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