TY - JOUR
T1 - Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity
AU - Laoukili, Jamila
AU - Constantinides, Alexander
AU - Wassenaar, Emma C. E.
AU - Elias, Sjoerd G.
AU - Raats, Danielle A. E.
AU - van Schelven, Susanne J.
AU - van Wettum, Jonathan
AU - Volckmann, Richard
AU - Koster, Jan
AU - Huitema, Alwin D. R.
AU - Nienhuijs, Simon W.
AU - de Hingh, Ignace H. J. T.
AU - Wiezer, René J.
AU - van Grevenstein, Helma M. U.
AU - Rinkes, Inne H. M. Borel
AU - Boerma, Djamila
AU - Kranenburg, Onno
N1 - Funding Information: This work was supported by grants from the Dutch Cancer Society (KWF2015-8088) to OK, and the Antonius Hospital Research Fund to DB. Publisher Copyright: © 2022, The Author(s).
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124940735&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41416-022-01742-5
DO - https://doi.org/10.1038/s41416-022-01742-5
M3 - Article
C2 - 35194192
SN - 0007-0920
VL - 126
SP - 1824
EP - 1833
JO - British journal of cancer
JF - British journal of cancer
IS - 12
ER -