Jae-Kyung Won1,2,†, Hee Won Yang3,†, Sung-Young Shin4,†, Jong Hoon Lee4, Won Do Heo3,* and Kwang-Hyun Cho1,4,*
1 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
2 Molecular Pathology Center, Seoul National University Cancer Hospital, Seoul 110-744, Korea
3 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
4 Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
*Correspondence: Kwang-Hyun Cho, Won Do Heo
† These authors contributed equally to this study.
MEK inhibitor has been highlighted as a promising anti-tumor drug but its effect has been reported as varying over a wide range depending on patho-physiological conditions. In this study, we employed a systems approach by combining biochemical experimentation with in silico simulations to investigate the resistance mechanism and functional consequences of MEK inhibitor. To this end, we have developed an extended integrative model of ERK and PI3K signaling pathways by considering the crosstalk between Ras and PI3K, and analyzed the resistance mechanism to MEK inhibitor under various mutational conditions. We found that phospho-Akt level under Raf mutation was remarkably augmented by MEK inhibitor while phospho-ERK level was almost completely repressed. These results suggest that bypassing of ERK signal to PI3K signal causes the resistance to MEK inhibitor in a complex oncogenic signaling network. We further investigated the underlying mechanism of the drug resistance and revealed that MEK inhibitor disrupts the negative feedback loops from ERK to SOS and GAB1, but activates the positive feedback loop composed of GAB1, Ras, and PI3K, which induces the bypass of ERK signal to PI3K signal. Based on these core feedback circuits, we suggested promising candidates for combination therapy and examined the improved inhibitory effects.
systems biology, mathematical model, ERK pathway, PI3K pathway, MEK inhibitor, resistance, robustness, biochemical control analysis