Zero-shot prediction of drug responses using biologically informed neural networks trained on phosphoproteomic timeseries.

Cellular signaling is driven by complex, dynamic phosphorylation networks that control growth and survival, and their dysregulation underlies diseases such as cancer. Although modern mass spectrometry enables large-scale quantification of phosphoproteomic responses over time, these measurements remain descriptive and cannot by themselves predict how signaling will evolve under perturbations. Here, we extend a biologically informed recurrent neural network framework (LEMBAS), to learn time-resolved phosphoproteomic trajectories. We introduce two interpretable modules; a phosphosite mapping that links signaling nodes to measured phosphorylation sites and a monotonic time mapping that aligns continuous experimental times to discrete signaling steps. Using synthetic benchmarks and an EGF-stimulation dataset with inhibitor treatments, the model accurately interpolates unseen time points and predicts drug-induced phosphoproteomic responses in a zero-shot setting, outperforming naïve and fully connected baselines. Importantly, the model identifies both canonical and non-canonical signaling effects, including modulation of the transcription factor FOXO3:S7 (from the PI3K/AKT pathway) by drugs affecting PTPN11 (from the RAS/ERK pathway). By combining mechanistic priors with deep learning, our framework provides a scalable approach to interpret and predict dynamic drug responses from phosphoproteomic data.