Panobinostat-Mediated inhibition of Pancreatic Stellate Cells: A Novel Strategy to Modulate the Tumor Microenvironment in PDAC

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibrotic stroma and by the active contribution of pancreatic stellate cells (PSCs), whose secretome promotes tumor progression, metastatic dissemination, and therapeutic resistance. Among the epigenetic modulators under investigation, the histone deacetylase inhibitor panobinostat (PAN) has shown potent antitumor activity across several malignancies; however, its efficacy and interaction with standard chemotherapeutics in PDAC remain poorly defined. In this study, we investigated the effects of panobinostat, alone and in combination with gemcitabine (GEM) or paclitaxel (PTX), in two biologically distinct PDAC models: the primary line PDAC3 and the highly migratory immortalized line PA-TU-8988T. We assessed cell migration (wound-healing assay), clonogenic capacity, drug sensitivity (SRB assay), and drug–drug interactions using the Chou–Talalay method. To examine the influence of the tumor microenvironment, parallel experiments were conducted in the presence of PSCconditioned medium (PSC-CM). Panobinostat exhibited strong cytotoxicity in the nanomolar range, with PDAC3 being the most sensitive line. PSC-CM significantly increased migration and clonogenic survival in both models, confirming the pro-tumoral influence of the stromal secretome. Panobinostat consistently reduced migration and colony formation and partially counteracted PSC-CMmediated enhancement of tumor aggressiveness. Drug-combination analysis revealed predominantly antagonistic interactions: PAN+GEM showed strong antagonism in both cell lines, whereas PAN+PTX displayed a milder but still non-synergistic profile. These pharmacodynamic patterns reflect the limited clinical efficacy of HDAC inhibitors combined with standard chemotherapy in PDAC, suggesting an intrinsic incompatibility beyond pharmacokinetic limitations. Overall, our findings demonstrate that PAN exerts robust anti-migratory and anti-clonogenic effects and can attenuate PSC-induced pro-tumoral signaling, highlighting its potential as a stromal-modulating agent. However, the absence of synergy with conventional chemotherapeutics underscores the need for alternative combination strategies, ideally integrating microenvironment-targeting approaches and more physiologically relevant preclinical models.