INTERNATIONAL CONGRESS OF
PharmacoGenetics
A Network Pharmacology Analysis of Synergistic Anti-Cancer Effects of Combined AXL and PARP Inhibition
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Sara Gholami,1,* Mohammadreza Mehraban,2 Amirsajad Jafari,3
1. Babol Branch. Islamic Azad University, Babol, Iran
2. Babol Branch. Islamic Azad University, Babol, Iran
3. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Introduction: Drug resistance remains a significant hurdle in cancer treatment. A promising strategy to overcome this is synthetic lethality, where simultaneously disrupting two molecular targets kills cancer cells even though hitting either one alone does not. Combining PARP inhibitors like Olaparib with AXL inhibitors like Bemcentinib seems to induce this lethal effect in cancer cells, yet the molecular reasons have been unclear. This study uses a network pharmacology approach to map the common targets and biological pathways modulated by these drugs to uncover the basis for their combined anti-cancer activity.
- Methods: We predicted potential protein targets for Bemcentinib and Olaparib using the SwissTargetPrediction database and identified the targets shared by both. These common proteins were used to construct a protein-protein interaction network with the STRING database. We then performed a Gene Ontology enrichment analysis to identify key molecular functions and biological processes. Finally, the network was analyzed in Cytoscape to identify central hub genes
- Results: A set of common protein targets for Bemcentinib and Olaparib was identified, including key regulators of cellular signaling and proliferation such as CDK1, CDK2, MAPK8, and SYK. The constructed PPI network revealed a highly interconnected cluster of these proteins. GO enrichment analysis demonstrated that these common targets are significantly involved in critical cancer-related functions and processes. Based on the Gene Ontology enrichment analysis, the gene set shows a highly significant enrichment for molecular functions and biological processes central to cancer biology. The results reveal a strong signature of dysregulated kinase signaling, including G protein-coupled receptor activity and protein serine/threonine kinase activity, which drive key processes such as peptidyl-serine phosphorylation, positive regulation of cell proliferation, and transmembrane receptor tyrosine kinase signaling. This pattern underscores the gene set's involvement in hallmark cancer pathways that sustain proliferative signaling, regulate cell survival, and modulate the tumor microenvironment, positioning these functions as potential mechanistic drivers and therapeutic targets. Inhibition of the apoptotic process. Topological analysis in Cytoscape identified several hub genes with high centrality scores. Notably, MAPK8, CDK1, CDK2, and SYK emerged as central nodes, indicating their critical role in mediating the network's biological effects.
- Conclusion: This network pharmacology analysis provides novel insights into the potential mechanisms driving the synthetic lethality observed with combined Bemcentinib and Olaparib treatment. Our findings suggest that the synergy does not only rely on the inhibition of AXL and PARP but also on the modulation of a shared network of targets critically involved in cell cycle progression and apoptosis. The identification of MAPK8, CDK1, and CDK2 as key hub proteins points towards the disruption of the cell cycle and stress-response pathways as a core mechanism. This dual-pronged attack may overwhelm the cancer cell's adaptive capabilities, leading to enhanced cell death and potentially preventing the development of drug resistance. These findings provide a strong rationale for the clinical combination of AXL and PARP inhibitors and highlight key targets for future experimental validation.
- Keywords: Bemcentinib, Olaparib, Drug Synergy, Cancer Therapy
