IDDF2019-ABS-0288 Fatty acid catabolism impacts the sensitivity of gastrointestinal cancers to platinum-based chemotherapy

Abstract

Background Carnitine palmitoyltransferases (CPTs) are capable of transporting fatty acids (FAs) into mitochondria to synthesize cardiolipin and initiate β-oxidation. The aim of this study was to identify the inhibition of CPT-mediated FA catabolism on oxaliplatin sensitivity and its therapeutic potential in gastrointestinal cancers. Methods We investigated oxaliplatin-induced metabolic alterations, disease control rates (DCRs) using gastric cancer (GC) and colorectal cancer (CRC) cells as well as CRC tissues from patients treated with FOLFOX or XELOX regimens (n = 82). The effects of CPT inhibitor perhexiline on the growth of GC and CRC were tested in vitro and in vivo. Results CPT1B and CPT2 were significantly upregulated when GC and CRC cells were treated with oxaliplatin, and increased CPT1B and CPT2 expression correlated with a worse DCR in patients receiving FOLFOX or XELOX. Suppression of CPT2 or delivering perhexiline inhibited the progression of GC and CRC cells by inducing apoptosis, which was due to the loss of cardiolipin, suppression of β-oxidation, destruction of mitochondrial membrane integrity and reduction in ATP production. This process enhanced the antitumor effect of oxaliplatin in vitro and in vivo. Especially, perhexiline treatment significantly suppressed the progression of GC and CRC in patient-derived xenograft (PDX) models, which was closely associated with CPT2 expression. Conclusions Activated expression of FA catabolism is related to the chemoresistance of patients with GC and CRC. Inhibition of CPT cooperates with oxaliplatin to suppress their growth, as CPT1B and CPT2 are potential biomarkers for platinum-based chemotherapy in GC and CRC.