Inhibition of Fatty Acid Synthase Upregulates Expression of CD36 to Sustain Proliferation of Colorectal Cancer Cells

Fatty acid synthase (FASN), a key enzyme in de novo lipogenesis, is a promising therapeutic target in cancer. The novel FASN inhibitor, TVB-3664, has shown anti-cancer activity across various cancers, including colorectal cancer. However, it remains unclear whether the uptake of exogenous fatty acids can counteract the effects of FASN inhibition. This study demonstrates that FASN inhibition selectively upregulates fatty acid translocase (CD36), a fatty acid transporter, in multiple colorectal cancer models. These models include colorectal cancer cells with shRNA-mediated FASN knockdown and genetically modified mouse tissues with heterozygous and homozygous FASN deletions. Additionally, human colorectal cancer tissues treated with TVB-3664 exhibit significant and selective upregulation of CD36 mRNA.

ShRNA-mediated knockdown of CD36 and inhibition of CD36 using sulfosuccinimidyl oleate, a chemical inhibitor, reduced cell proliferation in vitro and inhibited tumor growth in subcutaneous xenograft models. Isogenic cell populations derived from patient-derived xenografts that express high levels of CD36 demonstrated a significantly enhanced ability to grow tumors in vivo. The tumor-promoting effect of CD36 was linked to increased levels of pAkt and survivin. Importantly, combinatorial treatment of primary and established colorectal cancer cells with TVB-3664 and sulfosuccinimidyl oleate showed a synergistic effect on cell proliferation.

In conclusion, our study reveals that CD36 upregulation may serve as a compensatory mechanism for FASN inhibition, and that targeting CD36 can enhance the efficacy of FASN-targeted therapies.