A new wave of innovations within the DNA damage response
Abstract Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-09-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01548-8 |
| _version_ | 1797556086537977856 |
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| author | Qi Li Wenyuan Qian Yang Zhang Lihong Hu Shuhui Chen Yuanfeng Xia |
| author_facet | Qi Li Wenyuan Qian Yang Zhang Lihong Hu Shuhui Chen Yuanfeng Xia |
| author_sort | Qi Li |
| collection | DOAJ |
| description | Abstract Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes could induce excessive DNA damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit to patients with breast cancer gene (BRCA) mutation or homologous recombination deficiency (HRD), which proves the concept of synthetic lethality in cancer treatment. Moreover, the other two scenarios of DDR inhibitor application, replication stress and combination with chemo- or radio- therapy, are under active clinical exploration. In this review, we revisited the progress of DDR targeting therapy beyond the launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, which could maintain the efficacy while mitigating side effects, may diversify the application scenarios of PARP inhibitor in clinic. Albeit with unavoidable on-mechanism toxicities, several small molecules targeting DNA damage checkpoints (gatekeepers) have shown great promise in preliminary clinical results, which may warrant further evaluations. In addition, inhibitors for other DNA repair pathways (caretakers) are also under active preclinical or clinical development. With these progresses and efforts, we envision that a new wave of innovations within DDR has come of age. |
| first_indexed | 2024-03-10T16:57:54Z |
| format | Article |
| id | doaj.art-489c7a4f871c4dc4aebfd6257a254f49 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-10T16:57:54Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-489c7a4f871c4dc4aebfd6257a254f492023-11-20T11:05:02ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-09-018112610.1038/s41392-023-01548-8A new wave of innovations within the DNA damage responseQi Li0Wenyuan Qian1Yang Zhang2Lihong Hu3Shuhui Chen4Yuanfeng Xia5Domestic Discovery Service Unit, WuXi AppTecDomestic Discovery Service Unit, WuXi AppTecDomestic Discovery Service Unit, WuXi AppTecDomestic Discovery Service Unit, WuXi AppTecDomestic Discovery Service Unit, WuXi AppTecDomestic Discovery Service Unit, WuXi AppTecAbstract Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes could induce excessive DNA damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit to patients with breast cancer gene (BRCA) mutation or homologous recombination deficiency (HRD), which proves the concept of synthetic lethality in cancer treatment. Moreover, the other two scenarios of DDR inhibitor application, replication stress and combination with chemo- or radio- therapy, are under active clinical exploration. In this review, we revisited the progress of DDR targeting therapy beyond the launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, which could maintain the efficacy while mitigating side effects, may diversify the application scenarios of PARP inhibitor in clinic. Albeit with unavoidable on-mechanism toxicities, several small molecules targeting DNA damage checkpoints (gatekeepers) have shown great promise in preliminary clinical results, which may warrant further evaluations. In addition, inhibitors for other DNA repair pathways (caretakers) are also under active preclinical or clinical development. With these progresses and efforts, we envision that a new wave of innovations within DDR has come of age.https://doi.org/10.1038/s41392-023-01548-8 |
| spellingShingle | Qi Li Wenyuan Qian Yang Zhang Lihong Hu Shuhui Chen Yuanfeng Xia A new wave of innovations within the DNA damage response Signal Transduction and Targeted Therapy |
| title | A new wave of innovations within the DNA damage response |
| title_full | A new wave of innovations within the DNA damage response |
| title_fullStr | A new wave of innovations within the DNA damage response |
| title_full_unstemmed | A new wave of innovations within the DNA damage response |
| title_short | A new wave of innovations within the DNA damage response |
| title_sort | new wave of innovations within the dna damage response |
| url | https://doi.org/10.1038/s41392-023-01548-8 |
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