Large Language Models Meet Biomedical Knowledge Graphs for Mechanistically Grounded Therapeutic Prioritization
This work addresses drug repurposing for biomedical researchers by providing a more mechanistically grounded prioritization method, though it is incremental as it builds on existing knowledge graph and language model approaches.
The paper tackles the problem of drug repurposing by distinguishing biologically plausible candidates from historically well-connected ones, introducing DrugKLM, a hybrid framework integrating biomedical knowledge graphs with large language models for mechanistic reasoning, which outperforms baselines like TxGNN and shows functional alignment with molecular phenotypes across 12 TCGA cancers.
Drug repurposing is often framed as a candidate identification task, but existing approaches provide limited guidance for distinguishing biologically plausible candidates from historically well-connected ones. Here we introduce DrugKLM, a hybrid framework that integrates biomedical knowledge graph structure with large language model-based mechanistic reasoning to enable mechanistically grounded therapeutic prioritization. Across benchmark datasets, DrugKLM outperforms knowledge graph-only and language model-only baselines, including TxGNN. Beyond improved recall, DrugKLM confidence scores exhibit functional alignment with molecular phenotypes: higher scores are associated with transcriptional signatures linked to improved survival across 12 TCGA cancers. The scoring framework preferentially captures biologically perturbational signals rather than historical indication patterns. Expert curation across five cancers further reveals systematic differences in prioritization behavior, with DrugKLM elevating candidates supported by coherent mechanistic rationale and disease-specific clinical context. Together, these results establish DrugKLM as an evidence-integrative framework that translates heterogeneous biomedical data into mechanistically interpretable and clinically grounded therapeutic hypotheses.