Details

Autor(en) / Beteiligte

• Laoukili, Jamila
• Constantinides, Alexander
• Wassenaar, Emma C. E.
• Elias, Sjoerd G.
• Raats, Danielle A. E.
• van Schelven, Susanne J.
• van Wettum, Jonathan
• Volckmann, Richard
• Koster, Jan
• Huitema, Alwin D. R.
• Nienhuijs, Simon W.
• de Hingh, Ignace H. J. T.
• Wiezer, René J.
• van Grevenstein, Helma M. U.
• Rinkes, Inne H. M. Borel
• Boerma, Djamila
• Kranenburg, Onno

Titel

Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity

Ist Teil von

• British journal of cancer, 2022-06, Vol.126 (12), p.1824-1833

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Background Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance. Experimental design We generated a biobank consisting of 35 primary tumour regions and 59 paired PM from 12 patients. All samples were analysed by RNA sequencing. We also generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin. Results PM displayed various hallmarks of aggressive CRC biology. The vast majority of PM and paired primary tumours belonged to the Consensus Molecular Subtype 4 (CMS4). PMDO cultures were resistant to oxaliplatin and expressed high levels of glutamate-cysteine ligase (GCLC) causing detoxification of oxaliplatin through glutathione synthesis. Genetic or pharmacological targeting of GCLC sensitised PMDOs to a 1-h exposure to oxaliplatin, through increased platinum-DNA adduct formation. Conclusions These results link oxaliplatin resistance of colorectal PM to their CMS4 status and high reducing capacity. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin.