Network modeling of MDM2 inhibitor-oxaliplatin combination reveals biological synergy in wt-p53 solid tumors

• Published in: Oncotarget 2011-05, Vol.2 (5), p.378-392
• Main Authors: Azmi, Asfar S, Banerjee, Sanjeev, Ali, Shadan, Wang, Zhiwei, Bao, Bin, Beck, Frances W J, Maitah, Main, Choi, Minsig, Shields, Tony F, Philip, Philip A, Sarkar, Fazlul H, Mohammad, Ramzi M
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Apoptosis - genetics; Carcinoma, Ductal - drug therapy; Carcinoma, Ductal - genetics; Carcinoma, Ductal - metabolism; Cell Line, Tumor; Computational Biology; Computer Simulation; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Drug Synergism; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Regulatory Networks; Humans; Indoles - administration & dosage; Indoles - pharmacology; Microarray Analysis; Molecular Targeted Therapy - trends; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - pharmacology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Platinum Compounds - administration & dosage; Platinum Compounds - pharmacology; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Research Papers; RNA, Small Interfering - genetics; Spiro Compounds - administration & dosage; Spiro Compounds - pharmacology; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.269

Earlier we had shown that the MDM2 inhibitor (MI-219) belonging to the spiro-oxindole family can synergistically enhance the efficacy of platinum chemotherapeutics leading to 50% tumor free survival in a genetically complex pancreatic ductaladenocarcinoma (PDAC) xenograft model. In this report, we have taken a systems and network modeling approach in order to understand central mechanisms behind MI219-oxaliplatin synergy with validation in PDAC, colon and breast cancer cell lines. Microarray profiling of drug treatments (MI-219, oxaliplatin or their combination) in capan-2 cells reveal a similar unique set of gene alterations that is duplicated in other solid tumor cells. As single agent, MI-219 or oxaliplatin induced alterations in 48 and 761 genes respectively. The combination treatment resulted in 767 gene alterations with emergence of 286 synergy unique genes. Ingenuity network modeling of combination and synergy unique genes showed the crucial role of five key local networks CREB, CARF, EGR1, NF-kB and E-Cadherin. Compared to single agents the combination treatment super induced p53 and p21 confirming functional synergy. Further, the network signatures were validated at the protein level in all three cell lines. Individually silencing central nodes in these five hubsinterfered with MI-219-oxaliplatin activity confirming their critical role in aiding p53 mediated apoptotic response. We anticipate that our MI219-oxaliplatin network blueprints can be clinically translated in the rationale design and application of this unique therapeutic combination in a genetically pre-defined subset of patients.