Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

• DOI: 10.1016/j.xcrm.2024.101523
• Publication Date: 2024-04-25T14:41:15Z
• Authors: Sanne Bootsma; Mark P.G. Dings; Job Kesselaar; Roxan F.C.P.A. He...; Kyah van Megesen; Alexander Constan...; Leandro Ferreira ...; Ellen Stelloo; Enzo M. Scutigliani; Bella Bokan; Arezo Torang; Sander R. van Hooff; Danny A. Zwijnenburg; Valérie M. Wouters; Vincent C.J. van ...; Laskarina J.K. Ga...; Lisanne E. Nijman; Adrian Logiantara; Veronique L. Veen...; Sophie Schlingemann; Sterre van Piggelen; Nicole van der Wel; Przemek M. Krawczyk; Johannes J. Platt...; Jurriaan B. Tuynman; Ignace H. de Hingh; Jan P.G. Klomp; Arthur Oubrie; Petur Snaebjornsson; Jan Paul Medema; Arlene L. Oei; Onno Kranenburg; Clara C. Elbers; Kristiaan J. Lenos; Louis Vermeulen; Maarten F. Bijlsma
• Keywords: 0303 health sciences; HIPEC; General Biochemistry,Genetics and Molecular Biology; oxidative phosphorylation; mesenchymal cancer cell; Hyperthermic Intraperitoneal Chemotherapy; molecular subtype; Article; elesclomol; Mitochondria; Rats; mitochondria; peritoneal metastases; Mice; 03 medical and health sciences; copper; Cell Line, Tumor; Animals; Humans; Female; Colorectal Neoplasms; Peritoneal Neoplasms

Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.