Lipidomics Profiling Reveals Differential Alterations after FAS Inhibition in 3D Colon Cancer Cell Culture Models

Cancerous
cells synthesize most of their lipids de novo to
keep up with their rapid growth and proliferation. Fatty acid
synthase (FAS) is a key enzyme in the lipogenesis pathway that is
upregulated in many cancers and has gained popularity as a druggable
target of interest for cancer treatment. The first FAS inhibitor discovered,
cerulenin, initially showed promise for chemotherapeutic purposes
until it was observed that it had adverse side effects in mice. TVB-2640
(Denifanstat) is part of the newer generation of inhibitors. With
multiple generations of FAS inhibitors being developed, it is vital
to understand their distinct molecular downstream effects to elucidate
potential interactions in the clinic. Here, we profile the lipidome
of two different colorectal cancer (CRC) spheroids treated with a
generation 1 inhibitor (cerulenin) or a generation 2 inhibitor (TVB-2640).
We observe that the cerulenin causes drastic changes to the spheroid
morphology as well as alterations to the lipid droplets found within
CRC spheroids. TVB-2640 causes higher abundances of polyunsaturated
fatty acids (PUFAs) whereas cerulenin causes a decreased abundance
of PUFAs. The increase in PUFAs in TVB-2640 exposed spheroids indicates
it is causing cells to die via a ferroptotic mechanism rather than
a conventional apoptotic or necrotic mechanism.