Tissue-aware elastic net decomposition reveals shared and lineage-specific drug response biomarkers

Motivation: Computational models that predict cancer drug response from genomic features are central to biomarker discovery, yet a recent audit found data leakage in 72% of 32 published methods, and complex models offer little interpretability while only modestly exceeding simple baselines under honest evaluation. Tissue lineage is a largely untapped source of legitimate inductive bias, but existing tissue-aware methods neither separate pan-cancer from lineage-specific signal nor report leakage-free performance. Results: We introduce the Data Shared Elastic Net (DSEN), a tissue-aware regression that decomposes each drug's model into a shared coefficient block common to all lineages and tissue-specific deviation blocks. Under leakage-free cross-validation across 265 drugs, 1,462 cell lines and 31 tissue lineages, DSEN improved mean squared error over a standard elastic net for 92.5% of drugs (mean 4.95%) while selecting 58% fewer stable shared features. Shared coefficients generalized to held-out tissues (59% tissue-level win rate) and recurrently recovered transferable pathway modules (p53, MAPK), whereas tissue blocks captured lineage markers such as the skin MITF/S100B program. The closest tissue-aware comparator, TG-LASSO, performed worse than the tissue-agnostic baseline (-13.8% mean MSE). Ablation shows tissue-aware modeling helps most when features are scarce, with no single modality dominating.