Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Yuewei Xu; Sarah Spear; Yurui Ma; Marc P. Lorentzen; Michael Gruet; Flora McKinney; Yitao Xu; Chiharu Wickremesinghe; Madelen R. Shepherd; Iain McNeish; Hector C. Keun; Anke Nijhuis

doi:10.1016/j.celrep.2023.113307

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Yuewei Xu, Sarah Spear, Yurui Ma, Marc P. Lorentzen, Michael Gruet, Flora McKinney, Yitao Xu, Chiharu Wickremesinghe, Madelen R. Shepherd, Iain McNeish, Hector C. Keun^*, Anke Nijhuis^*

^*Corresponding author for this work

Imperial College London

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

6 Citations (Scopus)

Abstract

Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.

Original language	English
Article number	113307
Journal	Cell Reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113307
Publication status	Published - 31 Oct 2023
Externally published	Yes

Keywords

combination therapy
CP: Cancer
DNA repair
homolougous recombination
ovarian cancer
ovarian high-grade serous carcinoma
PARP inhibitor
RNA splicing

UN SDGs

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

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10.1016/j.celrep.2023.113307

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Xu, Y., Spear, S., Ma, Y., Lorentzen, M. P., Gruet, M., McKinney, F., Xu, Y., Wickremesinghe, C., Shepherd, M. R., McNeish, I., Keun, H. C., & Nijhuis, A. (2023). Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma. Cell Reports, 42(10), Article 113307. https://doi.org/10.1016/j.celrep.2023.113307

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title = "Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma",

abstract = "Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.",

keywords = "combination therapy, CP: Cancer, DNA repair, homolougous recombination, ovarian cancer, ovarian high-grade serous carcinoma, PARP inhibitor, RNA splicing",

author = "Yuewei Xu and Sarah Spear and Yurui Ma and Lorentzen, {Marc P.} and Michael Gruet and Flora McKinney and Yitao Xu and Chiharu Wickremesinghe and Shepherd, {Madelen R.} and Iain McNeish and Keun, {Hector C.} and Anke Nijhuis",

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year = "2023",

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day = "31",

doi = "10.1016/j.celrep.2023.113307",

language = "English",

volume = "42",

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T1 - Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

AU - Xu, Yuewei

AU - Spear, Sarah

AU - Ma, Yurui

AU - Lorentzen, Marc P.

AU - Gruet, Michael

AU - McKinney, Flora

AU - Xu, Yitao

AU - Wickremesinghe, Chiharu

AU - Shepherd, Madelen R.

AU - McNeish, Iain

AU - Keun, Hector C.

AU - Nijhuis, Anke

PY - 2023/10/31

Y1 - 2023/10/31

N2 - Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.

AB - Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.

KW - combination therapy

KW - CP: Cancer

KW - DNA repair

KW - homolougous recombination

KW - ovarian cancer

KW - ovarian high-grade serous carcinoma

KW - PARP inhibitor

KW - RNA splicing

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DO - 10.1016/j.celrep.2023.113307

M3 - Article

C2 - 37858464

AN - SCOPUS:85174338496

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 113307

ER -

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Abstract

Keywords

UN SDGs

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