Abstract Ionizing radiation (IR) is frequently used in the treatment of a variety of malignant tumors of different origins and stages. In recent years, numerous studies have demonstrated that interfering with signaling via growth factor receptor tyrosine kinases (RTKs) can increase the sensitivity of certain tumors to IR. The RTK for hepatocyte growth factor MET is aberrantly activated in numerous types of human malignancies. MET inhibition has been shown to synergize with DNA damaging agents in generation of DNA damage and to interfere with damage repair. In this study, we aimed to explore how the cellular response to ionizing radiation is modulated by MET inhibition. We have conducted an immunoaffinity-based LC-MS/MS phosphoproteomics survey study to explore the cellular phosphoproteome following exposure of MET-addicted cancer cells to MET inhibition alone and in combination with IR. Phosphorylation sites of interest have been examined using selected reaction monitoring (SRM) and further validated in vitro and in vivo by Western blotting and immunohistochemistry, respectively. Analysis of the survey data has identified more than 300 phosphopeptides which have changed in one experimental condition or more. Several of these phosphorylation changes have been confirmed and further investigated by targeted proteomics. These results have pointed to a sub-network of the DNA damage response (DDR) that is modulated in MET-addicted cancer cells upon DNA damage and MET inhibition. The resulting molecular signature present solely in MET-addicted systems could be responsible for the synergism observed between MET inhibition and DNA-damaging agents. We believe that these results will aid in understanding as how MET signaling crosstalks with the DDR with subsequent translational therapeutic clinical applications. Citation Format: Ariel Bensimon, Yitzhak Zimmer, Paola Francica, Jonas P. Koch, Astrid A. Glück, Daniel M. Aebersold, Ruedi Aebersold, Michaela Medova. The DNA damage-induced phosphoproteome is modulated by inhibition of the MET receptor. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A20.