Transformation of NSCLC to SCLC: Insights into Molecular Alterations, Tumor Origin, and Therapeutic Advancements

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, accounting for 15% of lung cancer cases worldwide. In recent years, the histological transformation from non-small-cell lung cancer (NSCLC) to SCLC has become a significant mechanism of acquired resistance, especially in patients undergoing treatment with tyrosine kinase inhibitors (TKIs) or immunotherapy. Although there is growing clinical understanding, the crucial biological mechanisms that drive this phenotypic switch are still not fully understood. Transformed SCLC (T-SCLC) seems to exhibit differences from de novo SCLC regarding molecular characteristics and tumor microenvironment, indicating unique evolutionary paths. While traditional chemotherapy has been the main treatment method after transformation, patient outcomes continue to be unsatisfactory, highlighting the necessity for a more profound mechanistic insight and the development of more effective treatments.