The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor
文献类型：期刊论文
| 刊名 | JOURNAL OF MOLECULAR CELL BIOLOGY
 |
| 出版日期 | 2012 |
| 卷号 | 4 |
| 关键词 | KINASE KINASE-1/2 INHIBITOR PHOSPHOINOSITIDE 3-KINASE-GAMMA ADVANCED CANCERS LUNG-CANCER CELL LUNG PHASE-II RESISTANCE ROBUSTNESS ACTIVATION MUTATIONS systems biology mathematical model ERK pathway PI3K pathway MEK inhibitor resistance robustness biochemical control analysis |
| ISSN号 | 1674-2788 |
| 其他题名 | The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor |
| 英文摘要 | 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 the MEK inhibitor under various mutational conditions. We found that the phospho-Akt level under the Raf mutation was remarkably augmented by MEK inhibitor, while the phospho-ERK level was almost completely repressed. These results suggest that bypassing of the ERK signal to the PI3K signal causes the resistance to the MEK inhibitor in a complex oncogenic signaling network. We further investigated the underlying mechanism of the drug resistance and revealed that the 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 the ERK signal to the PI3K signal. Based on these core feedback circuits, we suggested promising candidates for combination therapy and examined the improved inhibitory effects. |
| 资助项目 | [National Research Foundation of Korea (NRF)] ; [Korean Government] ; [Ministry of Education, Science & Technology (MEST)] ; [WCU (World Class University) through the NRF] ; [MEST] |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4561085 |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/51042]  |
| 专题 | 中国科学院合肥物质科学研究院 |
| 推荐引用方式 GB/T 7714 | . The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor[J]. JOURNAL OF MOLECULAR CELL BIOLOGY,2012,4. |
| APA | (2012).The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor.JOURNAL OF MOLECULAR CELL BIOLOGY,4. |
| MLA | "The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor".JOURNAL OF MOLECULAR CELL BIOLOGY 4(2012). |
入库方式： OAI收割
来源：合肥物质科学研究院
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