FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response

Altered lipid metabolism is a potential targetable metabolic vulnerability in colorectal cancer (CRC). Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Here, by using samples from a window trial of TVB-2640 treatment in CRC patients, we found that FASN inhibition induced DNA damage but impaired the DNA damage response (DDR). In colon cancer cell lines and patient-derived organoids, FASN inhibition potentiated chemotherapy-induced double-strand DNA breaks (DSBs) and apoptotic cell death by altering histone acetylation levels. In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation. Mechanistically, FASN inhibition attenuated activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to -H2AX foci in an acetylation-dependent manner. Moreover, FASN inhibition mediated DNA repair deficiency induced synthetic lethality with PARP inhibition in CRC cells. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.