Project Targeting p90 ribosomal S6 kinase to improve radiotherapy of breast cancer

Basic data

Title:
Targeting p90 ribosomal S6 kinase to improve radiotherapy of breast cancer
Duration:
01/12/2019 to 31/12/2020
Abstract / short description:
Y-box binding protein 1 (YB-1) is overexpressed in a variety of cancers including breast cancer and is associated with significantly lower overall- and disease-free survival as well as resistance to chemoradiotherapy. Exposure to ionizing radiation (IR) as well as the expression of oncogenes, i.e. mutated KRAS stimulates YB-1 phosphorylation at Ser-102. This phosphorylation of YB-1 is crucial to the repair IR-induced double strand breaks (DSB) and radioresistance. Likewise, YB-1 phosphorylation, either after exposure to IR or intrinsically through KRAS mutation depends greatly on activation by p90 ribosomal S6 kinase (RSK). The RSK family consists of four isoforms (RSK1-4) that regulate a variety of key cellular processes. RSK expression and activity are dysregulated in several malignancies, including breast, prostate, and lung cancer. Thus, based on dysregulation of YB-1 in cancers and the function of RSK in YB-1 phosphorylation, RSK can be a promising therapeutic target in combination with radiotherapy. Inhibition of YB-1 activation by pan RSK inhibitor LJI308 impairs the repair of IR-induced DSB in cancer cells. However, the effect is diminished by activation of DNA-repair mediator AKT after blockage of the YB-1/RSK pathway. Thus, dual targeting of RSK and AKT can be an efficient approach to block DNA repair and induce radiosensitivity of solid tumors. In this study, the expression pattern of RSK isoforms, the effect of each RSK isoform on cell proliferation and post-irradiation cell survival as well as the effect of RSK/AKT co-targeting on DSB repair and radiotherapy response will be investigated in vitro and ex vivo.

Involved staff

Managers

Faculty of Medicine
University of Tübingen
Faculty of Medicine
University of Tübingen

Local organizational units

Department of Radiation Oncology
Hospitals and clinical institutes
Faculty of Medicine

Funders

Tübingen, Baden-Württemberg, Germany
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