Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors
Targeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibito...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.885186/full |
| _version_ | 1818005985178943488 |
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| author | Peng Gu Liting Xue Chunyan Zhao Wenjing Li Zhen Jiang Aiguo Liu Tingting Li Lu Liu Markus Decker Xiaoxuan Cheng Wenqing Yang Renhong Tang |
| author_facet | Peng Gu Liting Xue Chunyan Zhao Wenjing Li Zhen Jiang Aiguo Liu Tingting Li Lu Liu Markus Decker Xiaoxuan Cheng Wenqing Yang Renhong Tang |
| author_sort | Peng Gu |
| collection | DOAJ |
| description | Targeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation. The lead compounds dramatically impaired human cancer cell growth, induced cell cycle arrest in S-phase, and resulted in elevated γH2AX. Furthermore, cancer cells became sensitized to chemotherapy and other DDR inhibitors. Dosed either as a single agent or in combination with cisplatin, the compounds significantly inhibited tumor growth in vivo. By upregulating ATR-CHK1 signaling, the RAD51 inhibitors increased surface PD-L1 levels in various tumor cells, suggesting a potential combination of RAD51 inhibitors with PD-1/PD-L1 blockade. Overall, our findings provide the preclinical rationale to explore RAD51 inhibitors as monotherapy or in combination with chemotherapy, immunotherapy or DDR-targeting therapy in cancer treatment. |
| first_indexed | 2024-04-14T04:54:17Z |
| format | Article |
| id | doaj.art-cd871d1b4fe440b0bb0d24c8c903e228 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T04:54:17Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-cd871d1b4fe440b0bb0d24c8c903e2282022-12-22T02:11:12ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-05-011210.3389/fonc.2022.885186885186Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 InhibitorsPeng Gu0Liting Xue1Chunyan Zhao2Wenjing Li3Zhen Jiang4Aiguo Liu5Tingting Li6Lu Liu7Markus Decker8Xiaoxuan Cheng9Wenqing Yang10Renhong Tang11State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaHigh School Sophomore, Hangzhou Foreign Languages School, Hangzhou, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaState Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, ChinaTargeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation. The lead compounds dramatically impaired human cancer cell growth, induced cell cycle arrest in S-phase, and resulted in elevated γH2AX. Furthermore, cancer cells became sensitized to chemotherapy and other DDR inhibitors. Dosed either as a single agent or in combination with cisplatin, the compounds significantly inhibited tumor growth in vivo. By upregulating ATR-CHK1 signaling, the RAD51 inhibitors increased surface PD-L1 levels in various tumor cells, suggesting a potential combination of RAD51 inhibitors with PD-1/PD-L1 blockade. Overall, our findings provide the preclinical rationale to explore RAD51 inhibitors as monotherapy or in combination with chemotherapy, immunotherapy or DDR-targeting therapy in cancer treatment.https://www.frontiersin.org/articles/10.3389/fonc.2022.885186/fullKeywords: RAD51small molecule inhibitorDNA damage responsehomologous recombinationsynthetic lethality |
| spellingShingle | Peng Gu Liting Xue Chunyan Zhao Wenjing Li Zhen Jiang Aiguo Liu Tingting Li Lu Liu Markus Decker Xiaoxuan Cheng Wenqing Yang Renhong Tang Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors Frontiers in Oncology Keywords: RAD51 small molecule inhibitor DNA damage response homologous recombination synthetic lethality |
| title | Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors |
| title_full | Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors |
| title_fullStr | Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors |
| title_full_unstemmed | Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors |
| title_short | Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors |
| title_sort | targeting the homologous recombination pathway in cancer with a novel class of rad51 inhibitors |
| topic | Keywords: RAD51 small molecule inhibitor DNA damage response homologous recombination synthetic lethality |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.885186/full |
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