Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints
© 2020, The Author(s). In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing syntheti...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/133093 |
| _version_ | 1826188680839036928 |
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| author | Kong, Yi Wen Dreaden, Erik C Morandell, Sandra Zhou, Wen Dhara, Sanjeev S Sriram, Ganapathy Lam, Fred C Patterson, Jesse C Quadir, Mohiuddin Dinh, Anh Shopsowitz, Kevin E Varmeh, Shohreh Yilmaz, Ömer H Lippard, Stephen J Reinhardt, H Christian Hemann, Michael T Hammond, Paula T Yaffe, Michael B |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Kong, Yi Wen Dreaden, Erik C Morandell, Sandra Zhou, Wen Dhara, Sanjeev S Sriram, Ganapathy Lam, Fred C Patterson, Jesse C Quadir, Mohiuddin Dinh, Anh Shopsowitz, Kevin E Varmeh, Shohreh Yilmaz, Ömer H Lippard, Stephen J Reinhardt, H Christian Hemann, Michael T Hammond, Paula T Yaffe, Michael B |
| author_sort | Kong, Yi Wen |
| collection | MIT |
| description | © 2020, The Author(s). In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment. |
| first_indexed | 2024-09-23T08:03:23Z |
| format | Article |
| id | mit-1721.1/133093 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:03:23Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1330932023-07-10T19:32:04Z Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints Kong, Yi Wen Dreaden, Erik C Morandell, Sandra Zhou, Wen Dhara, Sanjeev S Sriram, Ganapathy Lam, Fred C Patterson, Jesse C Quadir, Mohiuddin Dinh, Anh Shopsowitz, Kevin E Varmeh, Shohreh Yilmaz, Ömer H Lippard, Stephen J Reinhardt, H Christian Hemann, Michael T Hammond, Paula T Yaffe, Michael B Koch Institute for Integrative Cancer Research at MIT Center for Precision Cancer Medicine Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Biological Engineering © 2020, The Author(s). In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment. 2021-10-25T17:00:12Z 2021-10-25T17:00:12Z 2020 2021-06-10T15:31:51Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133093 Kong, Yi Wen, Dreaden, Erik C, Morandell, Sandra, Zhou, Wen, Dhara, Sanjeev S et al. 2020. "Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints." Nature Communications, 11 (1). en 10.1038/S41467-020-17958-Z Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Kong, Yi Wen Dreaden, Erik C Morandell, Sandra Zhou, Wen Dhara, Sanjeev S Sriram, Ganapathy Lam, Fred C Patterson, Jesse C Quadir, Mohiuddin Dinh, Anh Shopsowitz, Kevin E Varmeh, Shohreh Yilmaz, Ömer H Lippard, Stephen J Reinhardt, H Christian Hemann, Michael T Hammond, Paula T Yaffe, Michael B Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints |
| title | Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints |
| title_full | Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints |
| title_fullStr | Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints |
| title_full_unstemmed | Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints |
| title_short | Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints |
| title_sort | enhancing chemotherapy response through augmented synthetic lethality by co targeting nucleotide excision repair and cell cycle checkpoints |
| url | https://hdl.handle.net/1721.1/133093 |
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