Lomitapide reduces viability and clonogenicity in hepatocellular carcinoma cells but enhances xenograft growth: The importance of the tumor microenvironment.

Lomitapide, a microsomal triglyceride transfer protein inhibitor approved for the treatment of homozygous familial hypercholesterolemia, has recently attracted interest as a potential anticancer agent because of its effects on lipid metabolism. Given the central role of lipid handling in hepatocellular carcinoma (HCC), we investigated the impact of lomitapide-mediated microsomal triglyceride transfer protein inhibition using complementary in vitro and in vivo models. Lomitapide induced intracellular lipid accumulation and reduced cell viability and clonogenicity in human HCC cell lines (Huh7 and HepG2) in a dose-dependent manner, without affecting cell migration. However, in a subcutaneous xenograft model, lomitapide treatment paradoxically promoted tumor growth, increasing tumor volume, weight, and proliferative markers, whereas apoptosis-related proteins remained unchanged. Tumors from lomitapide-treated mice exhibited enhanced extracellular signal-regulated kinase (ERK) signaling and increased lipid accumulation, alongside reduced systemic lipoprotein levels. To reconcile these opposing effects, we examined the contribution of the tumor microenvironment. Coculture experiments revealed reduced sensitivity of HCC cells to lomitapide in the presence of nonparenchymal cells. Conditioned media studies identified hepatic stellate cells as key mediators of this resistance, associated with increased secretion of interleukin 8 and vascular endothelial growth factor after lomitapide exposure. These factors are known activators of proliferative signaling pathways in HCC. Collectively, our findings demonstrate that lomitapide exerts direct antiproliferative effects on HCC cells under simplified conditions, but promotes tumor growth in vivo through microenvironment-dependent mechanisms. This study highlights the critical influence of stromal-tumor interactions on therapeutic outcomes and urges caution in repurposing lipid-modulating drugs for cancer treatment without accounting for tissue context. SIGNIFICANCE STATEMENT: This study demonstrates that inhibition of microsomal triglyceride transfer protein exerts opposite effects on hepatocellular carcinoma depending on biological context, suppressing tumor cell growth in vitro while promoting tumor expansion in vivo. These findings reveal a decisive role for the tumor microenvironment, particularly stromal cell-derived protumorigenic signals, in shaping therapeutic responses to lipid-modulating drugs.