ArticleCancer discovery2022
Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Risk factors for brain metastasis in lung cancer: an umbrella review of systematic reviews and meta-analyses.BMJ open · 2025Pooled it
- Metabolites and cancer metastasis.Oncogene · 2026Review
- Retinoic acid in health and disease.Signal transduction and targeted therapy · 2026Review
- P2RY6Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Future directions in the treatment of brain metastases: evaluating the role of cellular players in the tumour microenvironment.Acta neuropathologica · 2026Review
- PMN-MDSCs-derived exosomal S100A9 drives breast cancer progression by enhancing cancer stemness and CXCL5-mediated metastatic potential.Cell death discovery · 2026Article
- Sphingosine-1-Phosphate Receptor 3 Confers Tumor Metastasis in Lung Cancer Resistant to Third-Generation EGFR Inhibitor.MedComm · 2026Article
- Pancancer Fine-Mapping of Mutational Intolerance Identifies CHEK1 as an Immunosuppressive Driver in Lung Adenocarcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting a super-enhancer induced aldehyde dehydrogenase metabolic loop mitigates CDK4/6 inhibitor resistance in estrogen receptor-positive cancers.Nature communications · 2026Article
- Cholesterol Promotes Lung Adenocarcinoma Brain Metastasis by Stabilizing EGFR Protein to Drive EMT, Metabolic Reprogramming, and Premetastatic Niche Formation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Serum S100A8/S100A9 is associated with increased risk of brain metastasis in patients with inflammatory breast cancer.medRxiv : the preprint server for health sciences · 2026Article
- Deciphering brain metastasis in epithelial ovarian cancer: multimodal analysis and potential biomarkers.NPJ precision oncology · 2026Article
- Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases.Annals of oncology : official journal of the European Society for Medical Oncology · 2025Article
- Retinol-driven Gene Signatures Predict Lung Adenocarcinoma Outcomes and Highlight PAICS as a Therapeutic Opportunity.Phenomics (Cham, Switzerland) · 2025Article
- Metabolic adaptations of brain metastasis.Nature reviews. Cancer · 2025Review
- ALDH1A1 in breast cancer: A prospective target to overcome therapy resistance (Review).Oncology letters · 2025Review
- A new, immunocompetent brain-metastatic mouse model of HER2-positive breast cancer.Clinical & experimental metastasis · 2025Article
- RBM10 deficiency promotes brain metastasis by modulating sphingolipid metabolism in a BBB model of EGFR mutant lung adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2025Article
- Regulation of metastatic organotropism.Trends in cancer · 2025Review
- Cancer brain metastasis: molecular mechanisms and therapeutic strategies.Molecular biomedicine · 2025Review
Corrections and comments
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Authors and funding
23 authors at 4 institutions in 1 country.
Funding
Abstract
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has significantly prolonged progression-free survival (PFS) in patients with EGFR-mutant lung cancer, including those with brain metastases. However, despite striking initial responses, osimertinib-treated patients eventually develop lethal metastatic relapse, often to the brain. Although osimertinib-refractory brain relapse is a major clinical challenge, its underlying mechanisms remain poorly understood. Using metastatic models of EGFR-mutant lung cancer, we show that cancer cells expressing high intracellular S100A9 escape osimertinib and initiate brain relapses. Mechanistically, S100A9 upregulates ALDH1A1 expression and activates the retinoic acid (RA) signaling pathway in osimertinib-refractory cancer cells. We demonstrate that the genetic repression of S100A9, ALDH1A1, or RA receptors (RAR) in cancer cells, or treatment with a pan-RAR antagonist, dramatically reduces brain metastasis. Importantly, S100A9 expression in cancer cells correlates with poor PFS in osimertinib-treated patients. Our study, therefore, identifies a novel, therapeutically targetable S100A9-ALDH1A1-RA axis that drives brain relapse. SIGNIFICANCE: Treatment with the EGFR TKI osimertinib prolongs the survival of patients with EGFR-mutant lung cancer; however, patients develop metastatic relapses, often to the brain. We identified a novel intracellular S100A9-ALDH1A1-RA signaling pathway that drives lethal brain relapse and can be targeted by pan-RAR antagonists to prevent cancer progression and prolong patient survival. This article is highlighted in the In This Issue feature, p. 873.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.