A reversible gene-targeting strategy identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo

Cell Rep. 2013 Nov 27;5(4):868-77. doi: 10.1016/j.celrep.2013.10.025. Epub 2013 Nov 14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / genetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Cisplatin / pharmacology*
  • DNA Damage / genetics
  • DNA Repair / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA Interference
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53 / genetics*
  • p38 Mitogen-Activated Protein Kinases / genetics

Substances

  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Cisplatin