In vivo Charakterisierung der Protein Kinase MK2 als potenzielles Zielmolekül für eine neue Chemotherapie-sensitivierende Krebstherapie

• Applicant: Professor Dr. Christian Reinhardt
• Subject Area: Hematology, Oncology
• Term: from 2009 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 154359109

In response to DNA damage cells activate a complex signaling network to arrest the cell cycle and repair DNA. Many components of this network have been found mutated in human cancers and many tumors show an impaired DNA damage response. Abrogation of the remaining checkpoint apparatus in combination with DNA-damaging chemotherapy has been proposed as a new therapeutic concept for chemosensitization. We identified MK2 as a checkpoint kinase specifically critical for the survival of p53-deficient tumor cells after DNA damage. This proposal aims to understand the activation mechanisms and the molecular details of MK2 function. We will use biochemical and genetic approaches to elucidate the role of MK2 for survival of p53-deficient cells after DNA damage. We will characterize MK2 as a target for checkpoint-abrogating therapy in combination with chemotherapy in vivo. The research plan is tailored to achieve four main goals: Characterization of mechanisms that govern MK2 activation after DNA damage. Identification of mRNAs that are posttranscriptionally stabilized by MK2 in response to DNA damage, and RNA-binding proteins involved in the stabilization of the identified mRNAs. We will characterize the role of MK2 as a tumor suppressor using an autochthonous model of lung cancer. We will use a knockin mouse amenable for specific MK2 inhibition to characterize the role of MK2 as a drug target for chemosensitizing therapy. The proposed experiments aim at characterizing MK2 as a drug target that will likely function synergistically with conventional DNAdamaging chemotherapy.

• DFG Programme: Independent Junior Research Groups