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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Molecular mechanisms and clinical insights in transformed small cell lung cancer: a narrative review
Xianzi Dai1, Yue Hao2, Jiaojiao Hong1
1Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine (Affiliated Hospital of Nanjing University of Chinese Medicine), Nanjing, China.
Background And Objective:
In recent years, the application of targeted therapies has significantly improved survival rates in patients with driver gene-positive non-small cell lung cancer (NSCLC). However, one mechanism underlying acquired resistance is the histological transformation from NSCLC to small cell lung cancer (SCLC). NSCLC-to-SCLC transformation is thought to occur due to selective pressure from targeted therapies, yet this shift has also been observed in patients receiving non-targeted treatments, raising questions about its underlying mechanisms. This review aims to identify key molecular biomarkers predictive of this transformation to optimize clinical management strategies for transformed SCLC (T-SCLC).
Methods:
We systematically searched PubMed, EMBASE, the Cochrane Library, and major international conference proceedings for all English-language articles published up to December 31, 2024. This review synthesizes current evidence on the mechanisms of T-SCLC transformation, its genomic and transcriptomic alterations, and related therapeutic approaches.
Key Content And Findings:
T-SCLC is hypothesized to involve tumor heterogeneity and lineage plasticity. Key molecular players include dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, NOTCH-ASCL1 signaling, mothers against decapentaplegic homolog 4 (SMAD4), SRY-related HMG-box 2 (SOX2), and epigenetic abnormalities such as histone modifications (methylation, acetylation, ubiquitination). Tumor protein p53 (TP53) and retinoblastoma 1 (RB1) inactivation may serve as predictive biomarkers, though causal relationships require validation. Post-transformation, chemotherapy remains the first-line treatment, while combining chemotherapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) improves progression-free survival.
Conclusions:
Current T-SCLC research is limited by retrospective designs and small sample sizes, leaving transformation mechanisms incompletely understood. This phenotypic shift highlights lung cancer plasticity as a novel resistance mechanism rooted in lineage plasticity and tumor heterogeneity. Personalized therapies guided by molecular profiling may represent a future direction for improving outcomes.
Insights
Histological transformation from non-small cell lung cancer to small cell lung cancer (SCLC) is a resistance mechanism. Identifying molecular biomarkers for transformed SCLC (T-SCLC) can optimize treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Targeted therapies improve survival in driver gene-positive non-small cell lung cancer (NSCLC).
- Acquired resistance can manifest as histological transformation from NSCLC to small cell lung cancer (SCLC).
- This transformation, termed T-SCLC, occurs under targeted and non-targeted treatments, necessitating understanding of its mechanisms.
Purpose of the Study:
- To identify key molecular biomarkers predictive of NSCLC-to-SCLC transformation.
- To optimize clinical management strategies for transformed SCLC (T-SCLC).
Main Methods:
- Systematic literature search of PubMed, EMBASE, Cochrane Library, and conference proceedings up to December 31, 2024.
- Synthesis of current evidence on T-SCLC transformation mechanisms, genomic/transcriptomic alterations, and therapeutic approaches.
Main Results:
- T-SCLC transformation involves tumor heterogeneity and lineage plasticity.
- Key molecular players include PI3K/AKT/mTOR, NOTCH-ASCL1, SMAD4, SOX2, and epigenetic abnormalities.
- TP53 and RB1 inactivation may be predictive biomarkers; chemotherapy +/- EGFR-TKIs are current treatments.
Conclusions:
- T-SCLC mechanisms are not fully understood due to study limitations (retrospective, small samples).
- Lung cancer plasticity and lineage plasticity drive this resistance mechanism.
- Personalized therapies based on molecular profiling are a future direction for improved outcomes.
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