Radiation-induced erbB-dependent activation of Akt-DNA-PKcs signaling and its role in radioresistance of solid tumors

• Applicant: Professor Dr. H. Peter Rodemann
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251207142

Previous research performed within the first funding period of the DFG-SFB 773 "Understanding and Overcoming Therapy Resistance of Solid Tumors" revealed that the erbB-receptor-dependent PI3K/Akt cascade is an important regulator of repair of radiation-induced DNA-double strand breaks (DNA-DSB). Thus, DNA repair signaling through this cascade seems to be a prominent feature of radioresistance of human solid tumors presenting overexpressed or mutated erbB receptors. In this context a direct protein-protein interaction between Akt1 and DNA-PKcs, which is the key enzyme of the Non-Homologous End-Joining repair mechanism (NHEJ) was described for the first time. Interaction of Akt1 and DNA-PKcs seems to be necessary for initiation, progression and termination of the NHEJ repair process. Moreover, recent data from other laboratories indicate a PI3K-independent activity of Akt in the NHEJ and potentially the homologous recombination (HR) repair mechanisms as well. Thus, the goal of the project is to identify the specific mechanisms by which Akt stimulates DNA-DSB repair in a PI3K-dependent and -independent manner. To elucidate the detailed mechanisms, the project will focus on the specific role of Akt isoforms activated via erbB-PI3K signaling in the cytoplasm and translocated to the nucleus as well as on the direct nuclear activation of Akt via MRE11 and ATM signaling. In addition to these basic research aspects addressed in vitro, studies on irradiated human tumor xenografts will exploit the efficacy of Akt and ATM antagonists on DNA-DSB repair in vivo. Understanding the specific role of PI3K-dependent and -independent Akt signaling in the regulation of the repair of radiotherapy-induced DNA-DSB may open novel targeting strategies to overcome radioresistance of human solid tumors.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Mahmoud Toulany