UNLABELLED: Lineage plasticity, a critical hallmark of cancer progression, enables tumor cells to evade inhibition of primary oncogenic pathways through histologic transformation. This adaptive process, driven by stemness-associated features and epigenetic reprogramming, poses significant challenges in treatment. Using non-small cell lung cancer and prostate cancer as models, we examine the utility of tissue and liquid biopsies in detecting histologic transformations and tailoring treatments to specific subtypes, which has profound clinical implications, potentially improving outcomes in patients with advanced, therapy-resistant disease. We also discuss emerging therapeutic strategies, including novel molecular targets, and address ongoing clinical challenges in managing treatment-emergent histologic transformation.

SIGNIFICANCE: The advent of highly effective molecularly targeted therapies results in increased recognition of treatment-emergent histologic transformation. This review not only summarizes current evidence on diagnosis and management of lineage plasticity but also explores therapeutic strategies under study, outlining a framework for clinical translation and successful drug development.