The mitochondrial disruptor devimistat (CPI-613®) synergizes with genotoxic anticancer drugs in colorectal cancer therapy in a Bim-dependent manner

Abstract

Colorectal cancer (CRC) is one of the most frequent tumor entities, with an increasing incidence and mortality in younger adults in Europe and the US. 5-year survival rates for advanced CRC are still low, highlighting the need for novel targets in CRC therapy. Here, we investigated the therapeutic potential of the compound devimistat (CPI 613®) that targets altered mitochondrial cancer cell metabolism and its synergism with the antineoplastic drugs 5-fluorouracil (5-FU) and irinotecan (IT) in CRC. Devimistat exerted a comparable cytotoxicity in a panel of established CRC cell lines and patient-derived short-term culture independent of their genetic and epigenetic status, whereas human colonic epithelial cells were more resistant indicating tumor selectivity. These findings were corroborated in intestinal organoid and tumoroid models. Mechanistically, devimistat disrupted mitochondrial membrane potential and severely impaired mitochondrial respiration, resulting in CRC cell death induction independent of p53. Combination treatment of devimistat with 5-FU or IT demonstrated synergistic cell killing in CRC cells as shown by Combenefit modelling and Chou-Talalay analysis. Increased cell death induction was revealed as major mechanism involving downregulation of anti-apoptotic genes and accumulation of pro-apoptotic Bim, which was confirmed by its genetic knockdown. In human CRC xenograft mouse models, devimistat showed anti-tumor activity and synergized with IT, resulting in prolonged survival and enhanced therapeutic efficacy. In human tumor xenografts, devimistat prevented IT-triggered p53 stabilization and caused synergistic Bim induction. Taken together, our study revealed devimistat as a promising candidate in CRC therapy by synergizing with established antineoplastic drugs in vitro and in vivo.