Model Guided Understanding Of Synergistic Combination Therapies In The Dna Damage Response Pathway

Most commonly used anti-cancer therapies involve the systemic administration of anti-proliferative and DNA damaging agents. Deregulation of DNA damage response (DDR) pathways can cause resistance to DNA damaging therapies. Synergistic combination strategies of novel DDR pathway modulators promise to re-sensitize to and amplify currently used standard-of-care therapies. Our goal is to gain mechanistic understanding of the DDR pathway by developing a predictive computational model using single cell microscopy phenotypic data and signaling data from a panel of cancer cell lines. We focus on synergistic and potentiating effects of drug combinations using standard-of-care drugs such as doxorubicin, gemcitabine and irinotecan, and DDR pathway modulators. Our computational model explains the mechanisms of synergistic or additive phenotype that are observed for various modulators and was validated using DDR signaling data. The presented computational model rationalizes the design of novel combination therapies targeting the DDR pathway, includes heterogeneity of different cell lines and is an important step towards the design of a biomarker strategy. Citation Format: Andreas Raue, Ozan Alkan, Daryl Drummond, Birgit Schoeberl. Model guided understanding of synergistic combination therapies in the DNA damage response pathway. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-34.