Molecular Landscape and Therapeutic Strategies of Lung Cancer Lineage Plasticity

Histologic transformation from lung adenocarcinoma (LUAD) to SCLC or lung squamous cell carcinoma (LUSC) represents distinct but converging processes of cellular plasticity. Cellular plasticity, the ability to switch phenotypes between distinct developmental lineages, is critical in embryogenesis, tissue repair, and homeostasis. Tumor cells exploit these mechanisms to adapt to external pressures, such as therapeutic interventions, resulting in phenotypic transitions that drive therapeutic resistance and poor prognosis. LUAD cells that undergo transformation to SCLC or LUSC demonstrate unique and overlapping genetic, transcriptomic, epigenetic, and immune microenvironment changes that underscore the convergence and divergence of these processes. Although the histologic transition of LUAD to SCLC and LUSC is increasingly recognized as a mechanism of resistance to targeted therapies in lung cancer, the molecular drivers of the transformation process remain poorly understood. This review highlights the current knowledge of the molecular drivers, transcriptional and epigenetic programs, and immune interactions underlying these transformations, offering insights into potential therapeutic targets to mitigate resistance mechanisms.