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. Fatty acid synthase (FASN), the rate-limiting enzyme of de novo lipogenesis, is an important regulator of colorectal cancer progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in preclinical studies, suggesting that combination strategies might be required to prolong patient survival. In this study, by using samples from a window trial of TVB-2640 treatment in patients with colorectal cancer, 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 and apoptotic cell death by altering histone acetylation. In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation. Mechanistically, FASN inhibition decreased activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to γH2AX foci in an acetylation-dependent manner. Moreover, FASN inhibition-mediated DNA repair deficiency induced synthetic lethality with PARP inhibition in colon cancer 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 colorectal cancer. SIGNIFICANCE: FASN inhibition attenuates DNA damage repair to potentiate the efficacy of chemotherapy and to promote synthetic lethality with PARP inhibitors, offering a potential combination strategy to reduce tumor recurrence in colorectal cancer.