Uncovering the Selective Drug Targets in Urethane-Mediated Lung Cancer through Network Approach

Aim: To identify the driver targets associated with urethane mediated tumorigenesis by pharmacokinetics prediction, target prediction and gene expression network analysis.

Methodology: Standard bioinformatics tools were used, which include SwissADME, SwissTargetPrediction, eXpression2Kinases (X2K), and ClustalO.

Results: It was found that urethane has very low lipophilicity and high gastrointestinal absorption. Urethane major probable targets include tyrosyl-DNA phosphodiesterase 1 (TDP1), acetyl cholinesterase and muscarinic acetylcholine receptors. Enrichment analysis showed that transcription factors most expressed through urethane-targeted genes include TRIM28, RELA, SUZ12 and EGR1 while protein-protein interaction analysis showed that these transcription factors were mostly coordinated by heat shock protein 90 (Hsp90) isoforms (HSP90AA1, HSPAB1 and HSP90B1). The implicated targets were highly associated with cyclin-dependent kinases (CDKs) and mitogen-activated protein kinases (MAPKs).

Conclusion: Selective inhibition of TDP1 and Hsp90 isoforms and not transcription factors, could be the central therapeutic point for suppression and prevention of lung tumour.