Lomitapide mesylate and lomitapide target ALDOA to inhibit growth and enhance gemcitabine efficacy in PDAC

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options. We performed a high-throughput viability screen in PDAC cell lines and identified lomitapide mesylate and lomitapide as potent candidates. In vitro, both compounds suppressed PDAC proliferation, induced G1 arrest, and promoted apoptosis. Mechanistically, proteomic and biochemical analyses identified fructose-bisphosphate aldolase A (ALDOA) as a direct target: lomitapide mesylate bound directly to active-site residues Arg-148, while lomitapide bound to active-site residues Lys-229 and Arg-148, lowering ALDOA catalytic activity. Consistent with this, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) decreased, leading to reduced ATP production and energy stress-mediated apoptosis. The observed synergistic or additive effects with gemcitabine depend on both specific PDAC cell line and chemical form of lomitapide, underscoring complexity of personalized combination therapies and need to consider drug properties and tumor biology. These findings support therapeutic repositioning of lomitapide mesylate and lomitapide for PDAC.