Abstract
AbstractThis white paper details the research conducted by Ignota Labs using their advanced causal and explainable AI technology,SAFEPATH, to analyse the mechanisms of hepatotoxicity for two EGFR-TKI inhibitors, Erlotinib and Gefitinib, the latter having an as yet unknown mechanism of toxicity. The known mechanism of UGT1A1-mediated toxicity of Erlotinib was recovered, and a novel sphingolipid metabolism mechansim of toxicity of Gefitinib was hypothesised and subsequently experimentally validated. Crucially, we were also able to suggest the reason for the observed heterogeneous toxicity response to Gefitinib. This study exemplifies the potential of integrating AI tools with comprehensive datasets to improve drug safety and patient management.
Publisher
Cold Spring Harbor Laboratory
Reference15 articles.
1. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans
2. N. I. of Diabetes, Digestive, and K. Diseases, Erlotinib. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Library of Medicine (US), 2018. Updated June 28, 2018.
3. N. I. of Diabetes, Digestive, and K. Diseases, Gefitinib. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Library of Medicine (US), 2018. Updated March 6, 2018.
4. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles