Large-scale AI-Ready Data for Anti-Cancer Drug Response Modeling

Drug response prediction (DRP) models are an active area of research in pharmacogenomics, with growing potential to accelerate the identification of effective anticancer drugs. However, their predictive performance is often constrained by limited dataset scale and insufficient coverages of cancer and chemical spaces. In addition, inconsistent benchmarking practices hinder reliable comparison across models. Standardized frameworks, such as the Innovative Methodologies and New Data for Predictive Oncology Model Evaluation (IMPROVE) project, provide unified data schemas and evaluation protocols for consistent benchmarking, but improving model generalizability requires larger and more diverse training data. In this work, we substantially expand the IMPROVE benchmark through large-scale integration of pharmacogenomic data, primarily from PharmacoDB, together with additional smaller data sources. The expanded resource includes millions of drug response measurements, broader multi-omics coverage, and a major increase in chemical diversity, adding more than 50,000 compounds. To evaluate the impact of the new dataset compared to the original IMPROVE benchmark dataset, we trained DRP models using the two datasets and assess their prediction performance using a common test set and several evaluation strategies, including drug-blind, cancer-blind, and disjoint data splits. While cancer-blind performance remained comparable to the original benchmark, models trained on the expanded dataset showed consistent improvements in drug-blind and disjoint settings, indicating enhanced generalization to previously unseen compounds. These results position the expanded dataset as a community resource that provides a richer foundation for developing DRP models intended to aid in the discovery of novel anticancer drugs.

Pharmacogenomic Knowledge Graph Augmentation for Graph Neural Network-Based Drug-Drug Interaction Prediction

Graph neural networks (GNNs) applied to drug-drug interaction (DDI) prediction rely exclusively on molecular structure encoded as SMILES-derived graphs. Prior work in this series demonstrated that model performance is bounded by the structural information content of training labels -- an Information Ceiling -- that architectural refinements alone cannot overcome. The present study investigates whether pharmacogenomic prior knowledge from the PharmGKB database partially closes this ceiling by providing metabolic pathway context that is independent of, and complementary to, molecular structure. Cytochrome P450 (CYP) enzyme substrate, inhibitor, and inducer annotations for four clinically relevant isoforms (CYP2D6, CYP3A4, CYP2C19, CYP2C9) are extracted and incorporated as a 12-dimensional feature vector concatenated to the molecular embedding prior to interaction prediction. Experiments are conducted under both pair-level and drug-level data splits to quantify generalization to unseen drugs. Results indicate that knowledge graph (KG) augmentation substantially improves DDI type classification under pair-level split conditions (F1-macro: 0.532 vs. 0.241 baseline), while binary interaction detection and drug-level generalization remain bounded by the Information Ceiling (AUC inflation: 0.224 vs. 0.250 baseline). Mechanistic validation on strictly held-out compounds confirms that augmentation preferentially improves CYP2C9-mediated interaction prediction, with probabilities increasing from 0.033-0.117 (baseline) to 0.560-0.586 (KG-augmented). An extension to single-molecule toxicity prediction on the Tox21 benchmark confirms that the effect is contingent on pharmacogenomic annotation coverage. These findings motivate the multimodal framework proposed for the subsequent study in this series.