title: Systems biology modeling reveals a possible mechanism of the tumor cell death upon oncogene inactivation in EGFR addicted cancers.
abstract: Despite many evidences supporting the concept of "oncogene addiction" and many hypotheses rationalizing it, there is still a lack of detailed understanding to the precise molecular mechanism underlying oncogene addiction. In this account, we developed a mathematic model of epidermal growth factor receptor (EGFR) associated signaling network, which involves EGFR-driving proliferation/pro-survival signaling pathways Ras/extracellular-signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3K)/AKT, and pro-apoptotic signaling pathway apoptosis signal-regulating kinase 1 (ASK1)/p38. In the setting of sustained EGFR activation, the simulation results show a persistent high level of proliferation/pro-survival effectors phospho-ERK and phospho-AKT, and a basal level of pro-apoptotic effector phospho-p38. The potential of p38 activation (apoptotic potential) due to the elevated level of reactive oxygen species (ROS) is largely suppressed by the negative crosstalk between PI3K/AKT and ASK1/p38 pathways. Upon acute EGFR inactivation, the survival signals decay rapidly, followed by a fast increase of the apoptotic signal due to the release of apoptotic potential. Overall, our systems biology modeling together with experimental validations reveals that inhibition of survival signals and concomitant release of apoptotic potential jointly contribute to the tumor cell death following the inhibition of addicted oncogene in EGFR addicted cancers.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Shi-Dong
authors.initials: SD
authors.lastname: Luo
authors.forename: You-Li
authors.initials: YL
authors.lastname: Pan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Pan
authors.initials: P
authors.lastname: Ji
authors.forename: Ze-Rong
authors.initials: ZR
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Ma
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D001205:Ascorbic Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000077156:Gefitinib; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D011799:Quinazolines; D017382:Reactive Oxygen Species; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid; D000077156:Gefitinib