Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers

SIMPLE SUMMARY: With the thriving efficacy of cancers to evolve and evade treatment strategies targeting the apoptosis cell death mechanism, it has become imperative to reorient these conventional cancer therapy methods. In this study, we opted for an in-silico approach to mine the essential non-apoptotic cell death genes. We holistically examined the extensive protein–protein interaction networks in three such cancers with poor prognosis: colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancer. Our analysis identified non-apoptotic cell death drug targets. ABSTRACT: Programed cell death or apoptosis fails to induce cell death in many recalcitrant cancers. Thus, there is an emerging need to activate the alternate cell death pathways in such cancers. In this study, we analyzed the apoptosis-resistant colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancers transcriptome profiles. We extracted clusters of non-apoptotic cell death genes from each cancer to understand functional networks affected by these genes and their role in the induction of cell death when apoptosis fails. We identified transcription factors regulating cell death genes and protein–protein interaction networks to understand their role in regulating cell death mechanisms. Topological analysis of networks yielded FANCD2 (ferroptosis, negative regulator, down), NCOA4 (ferroptosis, up), IKBKB (alkaliptosis, down), and RHOA (entotic cell death, down) as potential drug targets in colon adenocarcinoma, glioblastoma multiforme, small cell lung cancer phenotypes respectively. We also assessed the miRNA association with the drug targets. We identified tumor growth-related interacting partners based on the pathway information of drug-target interaction networks. The protein–protein interaction binding site between the drug targets and their interacting proteins provided an opportunity to identify small molecules that can modulate the activity of functional cell death interactions in each cancer. Overall, our systematic screening of non-apoptotic cell death-related genes uncovered targets helpful for cancer therapy.