期刊
CELL REPORTS
卷 5, 期 4, 页码 868-877出版社
CELL PRESS
DOI: 10.1016/j.celrep.2013.10.025
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资金
- Austrian Science Fund (FWF) [J 2900-B21]
- NIH [ES015339, GM60594, GM59281, CA112967]
- Janssen Pharmaceutical (Transcend)
- Koch Institute and Center for Environmental Health Sciences Core Grants [P30-CA14051, ES-002109]
- Volkswagenstiftung (Lichtenberg Program)
- Deutsche Forschungsgemeinschaft [SFB-832/A21, KFO-286/RP2, RE2246/2-1]
- Ministry for Science and Technology
- NRW [313-005-0910-0102]
- Deutsche Jose Carreras Leukamie Stiftung [DJCLS R12/26]
- Anna Fuller Fund
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.
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