ArticleJournal of hematology & oncology2021
Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation.
Article in Journal of hematology & oncology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 90 citations in OpenAlex.
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- Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies.JTO clinical and research reports · 2026Review
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- Lineage plasticity: a new dilemma in lung cancer treatment.Molecular biology reports · 2026Review
- Current Insights and Future Directions of Multiomic and Spatial-Omic Analysis in Non-Small Cell Lung Cancer.JCO precision oncology · 2026Review
- Paligenosis: dual potential of mature cell plasticity in regeneration and tumorigenesis.MedScience · 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
- Unveiling the roles of SPP1Genes & diseases · 2026Article
- Lineage plasticity and histological transformation: tumor histology as a spectrum.Cell research · 2025Review
- Article
- Unraveling the molecular-pathological characteristics and cellular complexity of the tumor immune microenvironment in metastatic non-small cell lung cancer.Cell communication and signaling : CCS · 2025Review
- Transcriptomic analysis reveals lung cancer and subtype-specific alternative splicing biomarkers regulated by RNA-binding proteins.Molecular therapy. Nucleic acids · 2025Article
- Histologic Transformation in Cancer: The Path for Clinical Translation.Cancer discovery · 2025Review
- Interpretable and integrative analysis of single-cell multiomics with scMKL.Communications biology · 2025Article
- Persistent lineage plasticity driving lung cancer development and progression.Clinical and translational medicine · 2025Review
- Molecular mechanisms and therapeutic strategies for small‑cell lung cancer transformation after TKI therapy in EGFR‑mutated lung adenocarcinoma (Review).Molecular and clinical oncology · 2025Review
- Complementary modes of resistance tobioRxiv : the preprint server for biology · 2025Article
- APOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer.Cancer research communications · 2025Article
Corrections and comments
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Authors and funding
30 authors at 1 institution in 1 country.
Funding
Abstract
backgroundLineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies.
methodsWe performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment.
resultsOur data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib.
conclusionsOur findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.
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