Abstract B2-27: Systems biological identification of optimal drug targets for combination therapy of non-small cell lung cancer

Abstract

Abstract Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, accounting for about 85% of all lung patients. Recently, molecularly targeted inhibitors of receptor tyrosine kinase (RTK) such as epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) signalling pathways have been highlighted as promising anti-tumor drugs because of the prevalence of genetic alterations within EGFR and FGFR signalling pathways in NSCLC patients. However, their functional effects have been reported as varying over a wide range depending on the patient-specific mutational conditions. To understand the underlying mechanism of the heterogeneous responses to EGFR and FGFR inhibitors and to find the optimal strategy for combination therapy, we have developed an integrative Boolean network model of EGFR, FGFR and DNA damage signalling pathways by integrating previous experimental evidences from the literature. Systematic perturbation analysis revealed that the multiple feedback regulations embedded in the signalling pathways play important roles in determining the responses to EGFR and FGFR inhibitors. We further analyzed the mechanism for the heterogeneous responses of cells to the EGFR and FGFR inhibitors under various mutational conditions and identified key genetic alterations that can lead to undesirable responses. Finally, extensive combinatorial perturbation analysis and subsequent comparison of the attractor profiles in the presence and absence of targeted inhibitors identified novel candidate drug targets for combinatorial therapy. Our analysis provides a new insight into the underlying mechanism of the heterogeneous cellular responses to EGFR and FGFR inhibitors and the optimal combinatorial treatment strategies. Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2014R1A2A1A10052404, 2013M3A9A7046303, and 2010-0017662) and by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. (HI13C2162). Citation Format: Jonghoon Lee, Kwang-Hyun Cho. Systems biological identification of optimal drug targets for combination therapy of non-small cell lung cancer. [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 B2-27.