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Updated: Jun 1, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Network modeling of MDM2 inhibitor-oxaliplatin combination reveals biological synergy in wt-p53 solid tumors
Asfar S Azmi1, Sanjeev Banerjee, Shadan Ali
1Department of Pathology, Wayne State University School of Medicine, MI, USA.
Abstract:
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.
Insights
The MDM2 inhibitor MI-219 combined with oxaliplatin shows synergistic effects in pancreatic ductal adenocarcinoma (PDAC) and other cancers. Network modeling identified key pathways crucial for this enhanced anti-cancer activity.
Area of Science:
- Oncology
- Systems Biology
- Pharmacology
Background:
- The MDM2 inhibitor MI-219 (spiro-oxindole family) synergistically enhances platinum chemotherapeutics.
- Previous studies demonstrated 50% tumor-free survival in pancreatic ductal adenocarcinoma (PDAC) xenografts.
Purpose of the Study:
- To elucidate the central mechanisms underlying the synergy between MI-219 and oxaliplatin using systems and network modeling.
- To validate these mechanisms in PDAC, colon, and breast cancer cell lines.
Main Methods:
- Microarray profiling of gene expression changes following treatment with MI-219, oxaliplatin, or their combination in capan-2 cells.
- Ingenuity network modeling of differentially expressed genes to identify key biological networks.
- Validation of network signatures at the protein level and assessment of functional roles via gene silencing.
Main Results:
- Combination treatment induced unique gene alterations, with 286 synergy-specific genes identified.
- Network modeling highlighted the critical roles of CREB, CARF, EGR1, NF-kB, and E-Cadherin networks.
- Combination therapy super-induced p53 and p21, with network hubs confirmed to be essential for p53-mediated apoptosis.
Conclusions:
- The MI-219-oxaliplatin combination exhibits functional synergy mediated by specific molecular networks.
- These network blueprints offer potential for clinical translation in designing rational therapeutic strategies for genetically selected cancer patients.
