Lineage plasticity: a new dilemma in lung cancer treatment.

Lineage plasticity, the ability of cancer cells to switch lineages, is an emerging and critical mechanism of therapy resistance in lung cancer, posing a major obstacle to durable treatment responses. This review synthesizes the latest clinical and mechanistic advances to provide an integrated framework for understanding this phenomenon. We first explore the cellular origins and the “lineage-sharing” hypothesis, explaining how distinct histologic subtypes can arise from overlapping progenitor compartments. We then delineate how therapeutic pressure, through intratumoral competition and epigenetic reprogramming, drives the selection and expansion of resistant clones manifesting as histologic transformation (e.g., NSCLC to SCLC, adenocarcinoma-to-squamous) or phenotypic switching (e.g., within SCLC). A dedicated analysis dissects the core molecular networks, centered on EGFR, KRAS, TP53/RB1, MYC, and SOX2, that orchestrate these lineage changes. Crucially, we highlight the direct clinical implications of plasticity, linking it to aggressive disease progression and poor patient outcomes. Finally, we discuss persistent challenges and future perspectives, emphasizing the need for biomarkers for early detection and novel therapeutic strategies aimed at constraining plasticity to overcome resistance.