Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year survival of only ∼13%. Despite incremental advances through combination chemotherapy, most patients relapse rapidly due to profound molecular heterogeneity and intrinsic resistance. Recent genomic and transcriptomic studies have defined distinct PDAC molecular subtypes, classical and basal-like, which differ in differentiation state, prognosis, and therapeutic vulnerability. Classical tumors, marked by GATA6 and hepatocyte nuclear factors, exhibit epithelial identity and relative chemosensitivity, whereas basal-like tumors driven by ΔNp63 and MYC display mesenchymal and inflammatory programs associated with resistance and poor outcome. Importantly, these subtypes are dynamic, with single-cell and spatial analyses revealing frequent coexistence and therapy-induced transitions, highlighting cellular plasticity as a major determinant of treatment response. Subtype identity is governed by lineage-defining transcription factors, chromatin regulators, and stromal cues that integrate to form reversible epigenetic states. Targeting these mechanisms with inhibitors of EZH2, BET proteins, or CDK9 can restore differentiation programs and resensitize tumors to chemotherapy. Integrating molecular subtyping with epigenetic modulation thus offers a rational path toward biomarker-guided therapy. Continued efforts combining spatially resolved profiling, organoid modeling, and liquid-biopsy monitoring will be essential to capture tumor evolution in real time. Understanding and therapeutically exploiting the transcriptional and epigenetic plasticity in PDAC may ultimately enable reprogramming of resistant states and improve clinical outcomes in this intractable disease.
Parassiadis et al. (Tue,) studied this question.