Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer

Tani, Masaru; Hatano, Koji; Ishizuya, Yu; Oka, Toshiki; Kanaki, Tomohiro; Inoguchi, Shunsuke; Yoshimura, Akihiro; Horibe, Yuki; Liu, Yutong; Nesrine, Sassi; Okuda, Yohei; Yamamoto, Akinaru; Uemura, Toshihiro; Yamamichi, Gaku; Hayashi, Takuji; Yamamoto, Yoshiyuki; Kato, Taigo; Kawashima, Atsunari; Yamaguchi, Takao; Obika, Satoshi; Yusa, Kosuke; Nonomura, Norio; Nimura, Keisuke

doi:https://doi.org/10.1111/cas.70194

Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer

Tani, Masaru; Hatano, Koji; Ishizuya, Yu et al.

Cancer Science, 2025

Number of Access:24（2025-11-27 00:43 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/102954

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Title	Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer
Creator	NRID 1000090981960 1000090981960 CreatorName Tani, Masaru
	NRID 1000060762234 1000060762234 ORCID 0000-0002-8409-5152 0000-0002-8409-5152 researchmap permalink koji_hatano koji_hatano Scopus Author ID 14627167600 14627167600 CreatorName Hatano, Koji
	NRID 1000000783854 1000000783854 ORCID 0000-0003-0778-1308 0000-0003-0778-1308 researchmap permalink okiishi okiishi Scopus Author ID 56509501000 56509501000 CreatorName Ishizuya, Yu
	NRID 1000060964385 1000060964385 CreatorName Oka, Toshiki
	NRID 1000091001460 1000091001460 Scopus Author ID 57211646513 57211646513 CreatorName Kanaki, Tomohiro
	CreatorName Inoguchi, Shunsuke
	NRID 1000070981992 1000070981992 CreatorName Yoshimura, Akihiro
	NRID 1000080981977 1000080981977 CreatorName Horibe, Yuki
	CreatorName Liu, Yutong
	CreatorName Nesrine, Sassi
	NRID 1000010964372 1000010964372 ORCID 0000-0001-9909-4200 0000-0001-9909-4200 researchmap permalink okudayohei okudayohei CreatorName Okuda, Yohei
	NRID 1000050909653 1000050909653 ORCID 0000-0002-3565-5870 0000-0002-3565-5870 researchmap permalink ayamamoto ayamamoto Scopus Author ID 57217430138 57217430138 CreatorName Yamamoto, Akinaru
	NRID 1000060905941 1000060905941 ORCID 0000-0001-5553-1640 0000-0001-5553-1640 Scopus Author ID 57089805900 57089805900 CreatorName Uemura, Toshihiro
	NRID 1000040882262 1000040882262 ORCID 0000-0003-2262-8141 0000-0003-2262-8141 researchmap permalink urology-osaka-japan urology-osaka-japan Scopus Author ID 56983033900 56983033900 CreatorName Yamamichi, Gaku
	NRID 1000050747079 1000050747079 researchmap permalink takuhaya takuhaya CreatorName Hayashi, Takuji
	NRID 1000090759557 1000090759557 ORCID 0000-0002-1271-3521 0000-0002-1271-3521 researchmap permalink yoshi229 yoshi229 CreatorName Yamamoto, Yoshiyuki
	NRID 1000070648021 1000070648021 ORCID 0000-0002-8681-1407 0000-0002-8681-1407 researchmap permalink taigokato taigokato Scopus Author ID 55414697500 55414697500 CreatorName Kato, Taigo
	NRID 1000050746568 1000050746568 ORCID 0000-0001-9369-4264 0000-0001-9369-4264 researchmap permalink akawashima akawashima Scopus Author ID 9846139400 9846139400 CreatorName Kawashima, Atsunari
	NRID 1000080596601 1000080596601 ORCID 0000-0003-3180-0257 0000-0003-3180-0257 researchmap permalink takao-yamaguchi takao-yamaguchi Scopus Author ID 56322895500 56322895500 CreatorName Yamaguchi, Takao
	NRID 1000080243252 1000080243252 ORCID 0000-0002-6842-6812 0000-0002-6842-6812 researchmap permalink read0014368 read0014368 Scopus Author ID 7003800550 7003800550 CreatorName Obika, Satoshi
	NRID 1000000813180 1000000813180 CreatorName Yusa, Kosuke
	NRID 1000030263263 1000030263263 researchmap permalink read0185096 read0185096 Scopus Author ID 7005880662 7005880662 CreatorName Nonomura, Norio
	NRID 1000000462713 1000000462713 CreatorName Nimura, Keisuke
Subject	CRISPR-Cas9 knockout screening
	LIG1 inhibitors
	PARP inhibitor
	prostate cancer
	synthetic lethality
Description	Tani M., Hatano K., Ishizuya Y., et al. Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer. Cancer Science (2025); https://doi.org/10.1111/cas.70194.
Abstract	Despite advances in androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase inhibitors (PARPIs), metastatic castration-resistant prostate cancer (mCRPC) remains lethal. PARPIs clinical efficacy is limited in patients with homologous recombination repair deficiencies, such as BRCA1/2 mutations, due to resistance. Thus, identifying novel synthetic lethal interactions with PARP may expand treatment options and improve therapeutic efficacy. Here, to identify genes that influence sensitivity to the PARPI olaparib, we conducted a genome-wide CRISPR-Cas9 knockout screening of 18,010 genes in DU145, 22Rv1, and LNCaP prostate cancer cell lines. Our screening identified PARP and LIG1 as synthetic lethality-inducing factors, whereas TP53 conferred resistance to PARPIs. Simultaneous inhibition of LIG1 and PARP increased DNA damage and apoptosis. Additionally, the combination of the LIG1 inhibitor L82-G17 with olaparib exhibited synergistic effects. To the best of our knowledge, we validated this combination therapy in vivo for the first time, suppressing tumor growth in a DU145 xenograft model while minimizing toxicity in normal tissues. Immunohistochemical analysis revealed that LIG1 was overexpressed in CRPC tissues, suggesting its potential as a therapeutic target. This study established LIG1 as a novel synthetic lethality-inducing factor in prostate cancer, showing that L82-G17 enhances the efficacy of olaparib, regardless of the BRCA mutation status. These findings suggest that the combination of PARP and LIG1 inhibitors could be a novel therapeutic strategy for mCRPC.
Publisher	John Wiley and Sons Inc
Source Title	Cancer Science
Date of Issued	2025-09-16
Language	English
Handle URL	https://hdl.handle.net/11094/102954
PISSN	13479032
eISSN	13497006
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1111/cas.70194
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Cancer Science. 2025
DC.title	Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer
DC.creator	Tani, Masaru
	Hatano, Koji
	Ishizuya, Yu
	Oka, Toshiki
	Kanaki, Tomohiro
	Inoguchi, Shunsuke
	Yoshimura, Akihiro
	Horibe, Yuki
	Liu, Yutong
	Nesrine, Sassi
	Okuda, Yohei
	Yamamoto, Akinaru
	Uemura, Toshihiro
	Yamamichi, Gaku
	Hayashi, Takuji
	Yamamoto, Yoshiyuki
	Kato, Taigo
	Kawashima, Atsunari
	Yamaguchi, Takao
	Obika, Satoshi
	Yusa, Kosuke
	Nonomura, Norio
	Nimura, Keisuke
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-09-16
DC.identifier	https://doi.org/10.1111/cas.70194
DC.subject	CRISPR-Cas9 knockout screening
	LIG1 inhibitors
	PARP inhibitor
	prostate cancer
	synthetic lethality
DC.description	Tani M., Hatano K., Ishizuya Y., et al. Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer. Cancer Science (2025); https://doi.org/10.1111/cas.70194.
DCTERMS.abstract	Despite advances in androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase inhibitors (PARPIs), metastatic castration-resistant prostate cancer (mCRPC) remains lethal. PARPIs clinical efficacy is limited in patients with homologous recombination repair deficiencies, such as BRCA1/2 mutations, due to resistance. Thus, identifying novel synthetic lethal interactions with PARP may expand treatment options and improve therapeutic efficacy. Here, to identify genes that influence sensitivity to the PARPI olaparib, we conducted a genome-wide CRISPR-Cas9 knockout screening of 18,010 genes in DU145, 22Rv1, and LNCaP prostate cancer cell lines. Our screening identified PARP and LIG1 as synthetic lethality-inducing factors, whereas TP53 conferred resistance to PARPIs. Simultaneous inhibition of LIG1 and PARP increased DNA damage and apoptosis. Additionally, the combination of the LIG1 inhibitor L82-G17 with olaparib exhibited synergistic effects. To the best of our knowledge, we validated this combination therapy in vivo for the first time, suppressing tumor growth in a DU145 xenograft model while minimizing toxicity in normal tissues. Immunohistochemical analysis revealed that LIG1 was overexpressed in CRPC tissues, suggesting its potential as a therapeutic target. This study established LIG1 as a novel synthetic lethality-inducing factor in prostate cancer, showing that L82-G17 enhances the efficacy of olaparib, regardless of the BRCA mutation status. These findings suggest that the combination of PARP and LIG1 inhibitors could be a novel therapeutic strategy for mCRPC.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
DC.format	102954
citation_title	Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer
citation_author	Tani, Masaru
	Hatano, Koji
	Ishizuya, Yu
	Oka, Toshiki
	Kanaki, Tomohiro
	Inoguchi, Shunsuke
	Yoshimura, Akihiro
	Horibe, Yuki
	Liu, Yutong
	Nesrine, Sassi
	Okuda, Yohei
	Yamamoto, Akinaru
	Uemura, Toshihiro
	Yamamichi, Gaku
	Hayashi, Takuji
	Yamamoto, Yoshiyuki
	Kato, Taigo
	Kawashima, Atsunari
	Yamaguchi, Takao
	Obika, Satoshi
	Yusa, Kosuke
	Nonomura, Norio
	Nimura, Keisuke
citation_publisher	John Wiley and Sons Inc
citation_language	English
citation_date	2025-09-16
citation_journal_title	Cancer Science
citation_doi	https://doi.org/10.1111/cas.70194
citation_public_url	https://hdl.handle.net/11094/102954

Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer

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