A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo
A fundamental limitation in devising new therapeutic strategies for killing cancer cells with DNA damaging agents is the need to identify synthetic lethal interactions between tumor-specific mutations and components of the DNA damage response (DDR) in vivo. The stress-activated p38 mitogen-activated...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2014
|
| Online Access: | http://hdl.handle.net/1721.1/90556 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-9547-3251 |
| _version_ | 1826191579276115968 |
|---|---|
| author | Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Mitra, Tanya Couvillon, Anthony D. Yaffe, Michael B. Cannell, Ian Gordon Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Morandell, Sandra M. Jacks, Tyler E Yaffe, Michael B |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Mitra, Tanya Couvillon, Anthony D. Yaffe, Michael B. Cannell, Ian Gordon Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Morandell, Sandra M. Jacks, Tyler E Yaffe, Michael B |
| author_sort | Reinhardt, H. Christian |
| collection | MIT |
| description | A fundamental limitation in devising new therapeutic strategies for killing cancer cells with DNA damaging agents is the need to identify synthetic lethal interactions between tumor-specific mutations and components of the DNA damage response (DDR) in vivo. The stress-activated p38 mitogen-activated protein kinase (MAPK)/MAPKAP kinase-2 (MK2) pathway is a critical component of the DDR network in p53-deficient tumor cells in vitro. To explore the relevance of this pathway for cancer therapy in vivo, we developed a specific gene targeting strategy in which Cre-mediated recombination simultaneously creates isogenic MK2-proficient and MK2-deficient tumors within a single animal. This allows direct identification of MK2 synthetic lethality with mutations that promote tumor development or control response to genotoxic treatment. In an autochthonous model of non-small-cell lung cancer (NSCLC), we demonstrate that MK2 is responsible for resistance of p53-deficient tumors to cisplatin, indicating synthetic lethality between p53 and MK2 can successfully be exploited for enhanced sensitization of tumors to DNA-damaging chemotherapeutics in vivo. |
| first_indexed | 2024-09-23T08:58:07Z |
| format | Article |
| id | mit-1721.1/90556 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:58:07Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/905562022-09-30T12:28:15Z A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Mitra, Tanya Couvillon, Anthony D. Yaffe, Michael B. Cannell, Ian Gordon Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Morandell, Sandra M. Jacks, Tyler E Yaffe, Michael B Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Morandell, Sandra Reinhardt, H. Christian Cannell, Ian Gordon Kim, Jacob S. Ruf, Daniela M. Mitra, Tanya Jacks, Tyler E. Yaffe, Michael B. A fundamental limitation in devising new therapeutic strategies for killing cancer cells with DNA damaging agents is the need to identify synthetic lethal interactions between tumor-specific mutations and components of the DNA damage response (DDR) in vivo. The stress-activated p38 mitogen-activated protein kinase (MAPK)/MAPKAP kinase-2 (MK2) pathway is a critical component of the DDR network in p53-deficient tumor cells in vitro. To explore the relevance of this pathway for cancer therapy in vivo, we developed a specific gene targeting strategy in which Cre-mediated recombination simultaneously creates isogenic MK2-proficient and MK2-deficient tumors within a single animal. This allows direct identification of MK2 synthetic lethality with mutations that promote tumor development or control response to genotoxic treatment. In an autochthonous model of non-small-cell lung cancer (NSCLC), we demonstrate that MK2 is responsible for resistance of p53-deficient tumors to cisplatin, indicating synthetic lethality between p53 and MK2 can successfully be exploited for enhanced sensitization of tumors to DNA-damaging chemotherapeutics in vivo. National Institutes of Health (U.S.) (Grant ES015339) National Institutes of Health (U.S.) (Grant GM60594) National Institutes of Health (U.S.) (Grant GM59281) National Institutes of Health (U.S.) (Grant CA112967) Janssen Pharmaceutical Ltd. Massachusetts Institute of Technology. Center for Environmental Health Sciences (Core Grant P30-CA14051) Massachusetts Institute of Technology. Center for Environmental Health Sciences (Core Grant ES-002109) 2014-10-02T18:43:04Z 2014-10-02T18:43:04Z 2013-11 2013-09 Article http://purl.org/eprint/type/JournalArticle 22111247 http://hdl.handle.net/1721.1/90556 Morandell, Sandra, H. Christian Reinhardt, Ian G. Cannell, Jacob S. Kim, Daniela M. Ruf, Tanya Mitra, Anthony D. Couvillon, Tyler Jacks, and Michael B. Yaffe. “A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions Between MK2 and P53 in the DNA Damage Response In Vivo.” Cell Reports 5, no. 4 (November 2013): 868–877. https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-9547-3251 en_US http://dx.doi.org/10.1016/j.celrep.2013.10.025 Cell Reports Creative Commons Attribution http://creativecommons.org/licenses/by-nc-nd/3.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Mitra, Tanya Couvillon, Anthony D. Yaffe, Michael B. Cannell, Ian Gordon Reinhardt, H. Christian Kim, Jacob S. Ruf, Daniela M. Morandell, Sandra M. Jacks, Tyler E Yaffe, Michael B A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo |
| title | A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo |
| title_full | A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo |
| title_fullStr | A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo |
| title_full_unstemmed | A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo |
| title_short | A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo |
| title_sort | reversible gene targeting strategy identifies synthetic lethal interactions between mk2 and p53 in the dna damage response in vivo |
| url | http://hdl.handle.net/1721.1/90556 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-9547-3251 |
| work_keys_str_mv | AT reinhardthchristian areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT kimjacobs areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT rufdanielam areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT mitratanya areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT couvillonanthonyd areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT yaffemichaelb areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT cannelliangordon areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT reinhardthchristian areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT kimjacobs areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT rufdanielam areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT morandellsandram areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT jackstylere areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT yaffemichaelb areversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT reinhardthchristian reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT kimjacobs reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT rufdanielam reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT mitratanya reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT couvillonanthonyd reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT yaffemichaelb reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT cannelliangordon reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT reinhardthchristian reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT kimjacobs reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT rufdanielam reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT morandellsandram reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT jackstylere reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo AT yaffemichaelb reversiblegenetargetingstrategyidentifiessyntheticlethalinteractionsbetweenmk2andp53inthednadamageresponseinvivo |