Lipid-Restricted Culture Media Reveal Unexpected Cancer Cell Sensitivities

Cancer
cell culture models frequently rely on fetal bovine
serum
as a source of protein and lipid factors that support cell survival
and proliferation; however, serum-containing media imperfectly mimic
the in vivo cancer environment. Recent studies suggest that typical
serum-containing cell culture conditions can mask cancer dependencies,
for example, on cholesterol biosynthesis enzymes, that exist in vivo
and emerge when cells are cultured in media that provide more realistic
levels of lipids. Here, we describe a high-throughput screen that
identified fenretinide and ivermectin as small molecules whose cytotoxicity
is greatly enhanced in lipid-restricted media formulations. The mechanism
of action studies indicates that ivermectin-induced cell death involves
oxidative stress, while fenretinide likely targets delta 4-desaturase,
sphingolipid 1, a lipid desaturase necessary for ceramide synthesis,
to induce cell death. Notably, both fenretinide and ivermectin have
previously demonstrated in vivo anticancer efficacy despite their
low cytotoxicity under typical cell culture conditions. These studies
suggest ceramide synthesis as a targetable vulnerability of cancer
cells cultured under lipid-restricted conditions and reveal a general
screening strategy for identifying additional cancer dependencies
masked by the superabundance of medium lipids.