ArticleMolecular systems biology2025
Phosphoproteomics of osimertinib-tolerant persister cells reveals targetable kinase-substrate signatures.
Article in Molecular systems biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Proteomic investigation of signaling dynamics: from static maps to network rewiring.Bioscience reports · 2026Review
- Heterogeneous, population-level drug-tolerant persisters exhibit ion-channel remodeling and ferroptosis susceptibility.bioRxiv : the preprint server for biology · 2026Article
- Tumor cell plasticity in non-small cell lung cancer: the role of microRNA and implications for diagnosis, prognosis and treatment.Translational cancer research · 2026Review
- Review
- Post-translational Modifications in Proteins: Prediction Methods, Biological Functions, and Diseases.MedComm · 2026Review
- Targeting tumor transition windows.Exploration of targeted anti-tumor therapy · 2026Review
- Mitochondrial niches of residual disease in EGFR-mutant NSCLC: immune-constrained persistence and therapeutic interception.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Osimertinib is the first-line therapy for EGFR-mutated non-small cell lung cancer, but acquired resistance emerges in most patients and remains a major barrier for complete cure. This phenomenon is most likely associated with the drug-tolerant persister (DTP) cell phenotype, a reversible state that enables survival under treatment and leads to irreversible drug resistance. To uncover the molecular mechanism driving this distinct phenotype, we applied data-independent acquisition mass spectrometry (DIA-MS) to establish the dynamic proteomic and phosphoproteomic landscape in the osimertinib DTPs. While osimertinib initially blocks EGFR signaling, ribosome synthesis and protein translation related pathways arise in DTP phase, and resistance developed through the reactivation of EGFR downstream pathways and anti-apoptotic mechanisms such as YAP1 and mTOR-BAD hyperphosphorylation, as validated by growth combination assays. Kinase enrichment revealed elevated phosphorylation of multiple CDK1 substrates in DTP phase and pharmacological or genetic inhibition of CDK1-mediated SAMHD1 activation significantly impair DTP growth and survival. This study illuminates the dynamic landscape underlying the DTPs biology and identifies biomarker and new targets to potentially prevent or delay the onset of resistance.
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Registered trials
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