Targeting RSK/YB-1 pathway to improve radiotherapy outcome of solid tumors

• Applicant: Professor Dr. Mahmoud Toulany
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290071447

Y-box binding protein-1 (YB-1) regulates a wide variety of cellular functions, including DNA repair, gene transcription, mRNA splicing, translation, and drug resistance. YB-1 is overexpressed in a variety of cancers and is associated with a significant lower overall- and disease-free survival as well as therapy resistance. YB-1 is one of the rare proteins that regulates cellular signaling pathways involved in all of the described cancer hallmarks. Cellular stress such as exposure to ionizing radiation (IR) and KRAS mutation enhance YB-1 phosphorylation at Ser-102 residue. So far, our data indicates that YB-1 stimulates repair of double strand break (DSB) through HR and A-NHEJ. Likewise, Ser-102 phosphorylation of YB-1 is crucial for DSB repair and radioresistance, most likely through regulating KAP1 expression. Additionally, we showed that the Ser-102 phosphorylation of YB-1, either through KRAS mutation or after exposure to IR depends on activation of ribosomal protein S6 kinase (RSK). RSK family consists of four isoforms that regulate key cellular processes. RSK isoforms are dysregulated in a variety of cancers including breast cancer and colorectal cancer. Thus, based on the deregulation of RSK and YB-1 in cancers and the function of RSK in YB-1 phosphorylation, RSK should be a promising therapeutic target in the combination with radiotherapy for the treatment of cancers, particularly those cancers characterized by oncogenic mutations in the components of RAS signaling pathway. Thus, the aim of this study is uncovering the function of RSK/YB-1 axis in DSB repair in vitro and in human tumor tissues ex vivo. In addition to these mechanistic basic research aspects, studies on irradiated human tumor xenografts will be performed to verify the role of RSK/YB-1 pathway in DSB repair and radiotherapy response in vivo by applying different targeting strategies. Insights from this study will provide the rational to test radiosensitizing effect of the most effective YB-1 targeting strategy in early phase clinical trials, especially, in breast- and colorectal cancer.

• DFG Programme: Research Grants