Targeting SUMOylation in ovarian cancer: sensitivity, resistance, and the role of MYC

Samantha Littler; Bethany Barnes; Rhys Owen; Louisa Nelson; Anthony Tighe; I-Hsuan Lin; Hugh Osborne; Christine Schmidt; Joanne Mcgrail; Stephen Taylor

doi:10.1016/j.isci.2025.112555

Targeting SUMOylation in ovarian cancer: sensitivity, resistance, and the role of MYC

Samantha Littler, Bethany Barnes, Rhys Owen, Louisa Nelson, Anthony Tighe, I-Hsuan Lin, Hugh Osborne, Christine Schmidt, Joanne Mcgrail, Stephen Taylor^*

^*Corresponding author for this work

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

Abstract

Cells overexpressing MYC depend on SUMOylation for survival and cell division. To assess the therapeutic potential of SUMO inhibition, we screened 30 patient-derived ovarian cancer models (OCMs) with the SUMO-activating enzyme inhibitor ML-792. While most were resistant, seven displayed intermediate sensitivity and a further five were particularly sensitive, with sensitivity accompanied by mitotic errors, polyploidy, apoptosis, and PML body expansion. Resistance was linked to ABCB1 upregulation, and inhibiting drug efflux sensitised eight resistant OCMs. MYC target genes were enriched in sensitive models, consistent with MYC being a potential driver of response. SUMO inhibition induced an adaptive transcriptional response in resistant cells, but this was attenuated in MYC-overexpressing cells, raising the possibility that transcriptional interference disrupts the homeostatic controls required to buffer inhibition of SUMO signalling. SUMO sensitivity did not overlap with PARP inhibitor sensitivity, supporting the therapeutic potential of apex SUMO inhibitors to target a subset of homologous-recombination-proficient ovarian cancers.

Original language	English
Article number	112555
Journal	iScience
Early online date	29 Apr 2025
DOIs	https://doi.org/10.1016/j.isci.2025.112555
Publication status	E-pub ahead of print - 29 Apr 2025

Keywords

SUMOylation
Ovarian cancer
Subasumstat
ABCB1
Drug resistance
Mitosis
Polyploidy
Transcriptional regulation
Cofactor squelching
SNIP1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2025.112555Licence: CC BY-NC-ND

NIHR Manchester Biomedical Research Centre
Bruce, I. (PI), Lord, G. (CoI), Lennon, R. (CoI), Black, G. (CoI), Wedge, D. (CoI), Morris, A. (CoI), Hussell, T. (CoI), Sharrocks, A. (CoI), Stivaros, S. (CoI), Buch, M. (CoI), Gough, J. (CoI), Kostarelos, K. (CoI), Thistlethwaite, F. (CoI), Kadler, K. (CoI), Barton, A. (CoI), Hyrich, K. (CoI), Mcbeth, J. (CoI), O'Neill, T. (CoI), Vestbo, J. (CoI), Simpson, A. (CoI), Singh, S. (CoI), Smith, J. (CoI), Felton, T. (CoI), Murray, C. (CoI), Griffiths, C. (CoI), Cullum, N. (CoI), Rhodes, L. (CoI), Warren, R. (CoI), Paus, R. (CoI), Dumville, J. (CoI), Viros Usandizaga, A. (CoI), Keavney, B. (CoI), Tomaszewski, M. (CoI), Allan, S. (CoI), Body, R. (CoI), Cartwright, E. (CoI), Heagerty, A. (CoI), Kalra, P. (CoI), Miller, C. (CoI), Rutter, M. (CoI), Smith, C. (CoI), Trafford, A. (CoI), Evans, D. (CoI), Crosbie, E. (CoI), Crosbie, P. (CoI), Harvie, M. (CoI), Howell, S. (CoI), Renehan, A. (CoI), Dive, C. (CoI), Blackhall, F. (CoI), Landers, D. (CoI), Krebs, M. (CoI), Cook, N. (CoI), Clarke, R. (CoI), Taylor, S. (CoI), Jorgensen, C. (CoI), Lorigan, P. (CoI), Jayson, G. (CoI), Valle, J. (CoI), Mccabe, M. (CoI), Armstrong, A. (CoI), Freitas, A. (CoI), Illidge, T. (CoI), Choudhury, A. (CoI), Hoskin, P. (CoI), West, C. (CoI), Van Herk, M. (CoI), Faivre-Finn, C. (CoI), Bristow, R. (CoI), Kirkby, K. (CoI), Birtle, A. (CoI), Mackay, R. (CoI), Radford, J. (CoI), Linton, K. (CoI), Higham, C. (CoI), Munro, K. (CoI), Plack, C. (CoI), Arden Armitage, C. (CoI), Bruce, I. (CoI), Moore, D. (CoI), Saunders, G. (CoI), Stone, M. (CoI), Haddock, G. (CoI), Lewis, S. (CoI), Elliott, R. (CoI), Green, J. (CoI), Lovell, K. (CoI), Morrison, A. (CoI), Shaw, J. (CoI), Bucci, S. (CoI), Ainsworth, J. (CoI), Webb, R. (CoI), Newman, W. (CoI), Banka, S. (CoI), Clayton-Smith, J. (CoI), Payne, K. (CoI), Moldovan, R. (CoI), Wynn, R. (CoI) & Jones, S. (CoI)
1/12/22 → 30/11/27
Project: Research

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@article{4f3ee692f68c46f69daef267f60b3ace,

title = "Targeting SUMOylation in ovarian cancer: sensitivity, resistance, and the role of MYC",

abstract = "Cells overexpressing MYC depend on SUMOylation for survival and cell division. To assess the therapeutic potential of SUMO inhibition, we screened 30 patient-derived ovarian cancer models (OCMs) with the SUMO-activating enzyme inhibitor ML-792. While most were resistant, seven displayed intermediate sensitivity and a further five were particularly sensitive, with sensitivity accompanied by mitotic errors, polyploidy, apoptosis, and PML body expansion. Resistance was linked to ABCB1 upregulation, and inhibiting drug efflux sensitised eight resistant OCMs. MYC target genes were enriched in sensitive models, consistent with MYC being a potential driver of response. SUMO inhibition induced an adaptive transcriptional response in resistant cells, but this was attenuated in MYC-overexpressing cells, raising the possibility that transcriptional interference disrupts the homeostatic controls required to buffer inhibition of SUMO signalling. SUMO sensitivity did not overlap with PARP inhibitor sensitivity, supporting the therapeutic potential of apex SUMO inhibitors to target a subset of homologous-recombination-proficient ovarian cancers. ",

keywords = "SUMOylation, Ovarian cancer, Subasumstat, ABCB1, Drug resistance, Mitosis, Polyploidy, Transcriptional regulation, Cofactor squelching, SNIP1",

author = "Samantha Littler and Bethany Barnes and Rhys Owen and Louisa Nelson and Anthony Tighe and I-Hsuan Lin and Hugh Osborne and Christine Schmidt and Joanne Mcgrail and Stephen Taylor",

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language = "English",

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AU - Littler, Samantha

AU - Barnes, Bethany

AU - Owen, Rhys

AU - Nelson, Louisa

AU - Tighe, Anthony

AU - Lin, I-Hsuan

AU - Osborne, Hugh

AU - Schmidt, Christine

AU - Mcgrail, Joanne

AU - Taylor, Stephen

PY - 2025/4/29

Y1 - 2025/4/29

N2 - Cells overexpressing MYC depend on SUMOylation for survival and cell division. To assess the therapeutic potential of SUMO inhibition, we screened 30 patient-derived ovarian cancer models (OCMs) with the SUMO-activating enzyme inhibitor ML-792. While most were resistant, seven displayed intermediate sensitivity and a further five were particularly sensitive, with sensitivity accompanied by mitotic errors, polyploidy, apoptosis, and PML body expansion. Resistance was linked to ABCB1 upregulation, and inhibiting drug efflux sensitised eight resistant OCMs. MYC target genes were enriched in sensitive models, consistent with MYC being a potential driver of response. SUMO inhibition induced an adaptive transcriptional response in resistant cells, but this was attenuated in MYC-overexpressing cells, raising the possibility that transcriptional interference disrupts the homeostatic controls required to buffer inhibition of SUMO signalling. SUMO sensitivity did not overlap with PARP inhibitor sensitivity, supporting the therapeutic potential of apex SUMO inhibitors to target a subset of homologous-recombination-proficient ovarian cancers.

AB - Cells overexpressing MYC depend on SUMOylation for survival and cell division. To assess the therapeutic potential of SUMO inhibition, we screened 30 patient-derived ovarian cancer models (OCMs) with the SUMO-activating enzyme inhibitor ML-792. While most were resistant, seven displayed intermediate sensitivity and a further five were particularly sensitive, with sensitivity accompanied by mitotic errors, polyploidy, apoptosis, and PML body expansion. Resistance was linked to ABCB1 upregulation, and inhibiting drug efflux sensitised eight resistant OCMs. MYC target genes were enriched in sensitive models, consistent with MYC being a potential driver of response. SUMO inhibition induced an adaptive transcriptional response in resistant cells, but this was attenuated in MYC-overexpressing cells, raising the possibility that transcriptional interference disrupts the homeostatic controls required to buffer inhibition of SUMO signalling. SUMO sensitivity did not overlap with PARP inhibitor sensitivity, supporting the therapeutic potential of apex SUMO inhibitors to target a subset of homologous-recombination-proficient ovarian cancers.

KW - SUMOylation

KW - Ovarian cancer

KW - Subasumstat

KW - ABCB1

KW - Drug resistance

KW - Mitosis

KW - Polyploidy

KW - Transcriptional regulation

KW - Cofactor squelching

KW - SNIP1

U2 - 10.1016/j.isci.2025.112555

DO - 10.1016/j.isci.2025.112555

M3 - Article

SN - 2589-0042

JO - iScience

JF - iScience

M1 - 112555

ER -

Targeting SUMOylation in ovarian cancer: sensitivity, resistance, and the role of MYC

Abstract

Keywords

UN SDGs

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NIHR Manchester Biomedical Research Centre

Cite this