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

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

doi:10.1038/s41416-022-01742-5

Abstract

BackgroundPeritoneal 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 designWe 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.ResultsPM 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.ConclusionsThese 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.

Highlights

Systemic chemotherapy of metastatic colorectal cancer has prolonged median overall survival to over 2 years
We previously demonstrated that Peritoneal metastases (PM)-derived organoids (PMDOs) from cancer patients are resistant to clinically relevant doses of oxaliplatin [12]
A biobank of peritoneal metastases with paired primary tumours and other distant metastases We prospectively generated a biobank of 94 paired tissue samples derived from patients with operable peritoneal metastases (PM)

Summary

Introduction

Systemic chemotherapy of metastatic colorectal cancer (mCRC) has prolonged median overall survival to over 2 years. Patients with metastases in the peritoneal cavity (peritoneal metastases, PM) have a significantly reduced benefit from systemic chemotherapy compared with metastases at other sites [1, 2] The mechanisms underlying this site-dependent variation in treatment benefit are unknown and may be related to differences in tumour biology and/or drug exposure. We have previously developed a novel 4-gene RTqPCR test to identify CMS4 tumours [4] By applying this test to a series of PM and paired primary tumours, we demonstrated an enrichment of CMS4 in this subgroup of CRC patients [5]. We generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin

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