Abstract

Background: The high costs, long development timelines, and low clinical success rates in oncology highlight an urgent need for reliable computational strategies for drug repositioning. Current machine learning approaches often integrate heterogeneous pharmacogenomic datasets, which may lose biological specificity and limit model interpretability. Methods: In this study, we propose Separate XAI, an explainable artificial intelligence framework that retains dataset-specific biological features by adopting separate preprocessing and training pipelines for the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets. Different deep learning architectures such as Deep Neural Networks (DNNs), Convolutional Neural Networks (CNNs), and Recurrent Neural Networks (RNNs) were used to predict the drug response in the cancer cell lines. We also used SHapley Additive exPlanations (SHAP) to improve interpretability and identify biologically relevant features. Results: The developed framework showed good predictions with 94.49% accuracy in the CCLE dataset and a mean squared error of 0.0725 in the GDSC dataset. Explainability analysis identified important biomarkers and signaling pathways such as TP53 and KRAS, providing mechanistic insights into drug sensitivity and therapeutic response. Conclusions: The distinct XAI presented here offers an interpretable, biologically grounded framework for cancer drug repositioning by integrating dataset-specific modeling and explainable artificial intelligence. However, integration-based approaches often suffer from confounding effects of experimental and biological heterogeneity, but the proposed framework explicitly preserves dataset-specific characteristics, which potentially could lead to more robust predictions and higher interpretability for precision oncology and translational cancer research.

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