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

J. Laoukili; A. Constantinides; E.C.E. Wassenaar; S.G. Elias; D.A.E. Raats; S.J. van Schelven; J. van Wettum; R. Volckmann; J. Koster; A.D.R. Huitema; S.W. Nienhuijs; I.H.J.T. de Hingh; R.J. Wiezer; H.M.U. van Grevenstein; I.H.M.B. Rinkes; D. Boerma; O. Kranenburg

doi:10.1038/s41416-022-01742-5

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

J. Laoukili, A. Constantinides, E.C.E. Wassenaar, S.G. Elias, D.A.E. Raats, S.J. van Schelven, J. van Wettum, R. Volckmann, J. Koster, A.D.R. Huitema, S.W. Nienhuijs, I.H.J.T. de Hingh, R.J. Wiezer, H.M.U. van Grevenstein, I.H.M.B. Rinkes, D. Boerma^*, O. Kranenburg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1824-1833
Number of pages	10
Journal	British Journal of Cancer
Volume	126
Issue number	12
Early online date	22 Feb 2022
DOIs	https://doi.org/10.1038/s41416-022-01742-5
Publication status	Published - 1 Jun 2022

Keywords

HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY
CYTOREDUCTIVE SURGERY
PRODIGE 7
CELLS
GLUTATHIONE
CLASSIFICATION
FIBROBLASTS
ACTIVATION
PROGNOSIS
ORGANOIDS

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Laoukili, J., Constantinides, A., Wassenaar, E. C. E., Elias, S. G., Raats, D. A. E., van Schelven, S. J., van Wettum, J., Volckmann, R., Koster, J., Huitema, A. D. R., Nienhuijs, S. W., de Hingh, I. H. J. T., Wiezer, R. J., van Grevenstein, H. M. U., Rinkes, I. H. M. B., Boerma, D., & Kranenburg, O. (2022). Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity. British Journal of Cancer, 126(12), 1824-1833. https://doi.org/10.1038/s41416-022-01742-5

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

abstract = "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.",

keywords = "HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY, CYTOREDUCTIVE SURGERY, PRODIGE 7, CELLS, GLUTATHIONE, CLASSIFICATION, FIBROBLASTS, ACTIVATION, PROGNOSIS, ORGANOIDS",

author = "J. Laoukili and A. Constantinides and E.C.E. Wassenaar and S.G. Elias and D.A.E. Raats and {van Schelven}, S.J. and {van Wettum}, J. and R. Volckmann and J. Koster and A.D.R. Huitema and S.W. Nienhuijs and {de Hingh}, I.H.J.T. and R.J. Wiezer and {van Grevenstein}, H.M.U. and I.H.M.B. Rinkes and D. Boerma and O. Kranenburg",

year = "2022",

month = jun,

day = "1",

doi = "10.1038/s41416-022-01742-5",

language = "English",

volume = "126",

pages = "1824--1833",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

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Laoukili, J, Constantinides, A, Wassenaar, ECE, Elias, SG, Raats, DAE, van Schelven, SJ, van Wettum, J, Volckmann, R, Koster, J, Huitema, ADR, Nienhuijs, SW, de Hingh, IHJT, Wiezer, RJ, van Grevenstein, HMU, Rinkes, IHMB, Boerma, D & Kranenburg, O 2022, 'Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity', British Journal of Cancer, vol. 126, no. 12, pp. 1824-1833. https://doi.org/10.1038/s41416-022-01742-5

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, J.

AU - Constantinides, A.

AU - Wassenaar, E.C.E.

AU - Elias, S.G.

AU - Raats, D.A.E.

AU - van Schelven, S.J.

AU - van Wettum, J.

AU - Volckmann, R.

AU - Koster, J.

AU - Huitema, A.D.R.

AU - Nienhuijs, S.W.

AU - de Hingh, I.H.J.T.

AU - Wiezer, R.J.

AU - van Grevenstein, H.M.U.

AU - Rinkes, I.H.M.B.

AU - Boerma, D.

AU - Kranenburg, O.

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.

KW - HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY

KW - CYTOREDUCTIVE SURGERY

KW - PRODIGE 7

KW - CELLS

KW - GLUTATHIONE

KW - CLASSIFICATION

KW - FIBROBLASTS

KW - ACTIVATION

KW - PROGNOSIS

KW - ORGANOIDS

U2 - 10.1038/s41416-022-01742-5

DO - 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 -