ArticleCancer research2024
ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.
Article in Cancer research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 24 citations in OpenAlex.
- Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies.JTO clinical and research reports · 2026Review
- Lineage plasticity: a new dilemma in lung cancer treatment.Molecular biology reports · 2026Review
- Advances in understanding the mechanisms underlying acquired resistance to third-generation tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in cell and developmental biology · 2026Review
- Squamous transformation of EGFR-mutant lung adenocarcinoma after EGFR-TKI therapy: clonal continuity, tissue-based diagnosis, and therapeutic evidence gaps.Frontiers in oncology · 2026Review
- Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification.Nature structural & molecular biology · 2026Article
- Mitochondrial niches of residual disease in EGFR-mutant NSCLC: immune-constrained persistence and therapeutic interception.Frontiers in immunology · 2026Review
- Persistent lineage plasticity driving lung cancer development and progression.Clinical and translational medicine · 2025Review
- EGFR-TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer.Cell death & disease · 2025Article
- Drug-induced tolerant persisters in tumor: mechanism, vulnerability and perspective implication for clinical treatment.Molecular cancer · 2025Review
- METTL16-dependent miR-146b-5p m6A modification remodeling sensitize NSCLC to osimertinib via activating PI3K/AKT signaling.BMC cancer · 2025Article
- The chemotherapy agent doxorubicin induces CNS expression of Ascl1, a regulator of adult neurogenesis and differentiation.Scientific reports · 2025Article
- Single-Cell RNA Sequencing in Unraveling Acquired Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: New Perspectives.International journal of molecular sciences · 2025Review
- Metabolic reprogramming signature predicts prognosis and immune landscape in small cell lung cancer: MOCS2 validation and implications for personalized therapy.Frontiers in molecular biosciences · 2025Article
- An integrative analysis of ASCL1 in breast cancer and inhibition of ASCL1 increases paclitaxel sensitivity by activating ferroptosis via the CREB1/GPX4 axis.Frontiers in immunology · 2025Article
- Targeting C797S mutations and beyond in non-small cell lung cancer-a mini-review.Translational cancer research · 2024Review
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
- A Path to Persistence after EGFR Inhibition.Cancer research · 2024Article
- The molecular determinants of phenotypic plasticity in homeostasis and neoplasia.Cancer heterogeneity and plasticity · 2024Article
- Identification of molecular subtypes based on chromatin regulator-related genes and experimental verification of the role of ASCL1 in conferring chemotherapy resistance to breast cancer.Frontiers in immunology · 2024Article
Corrections and comments
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Authors and funding
20 authors at 2 institutions in 1 country.
Funding
Abstract
The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors. SIGNIFICANCE: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188.
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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.