Molecular mechanisms and clinical insights in transformed small cell lung cancer: a narrative review.

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.