Drug sensitivity prediction across cancer types using graph isomorphism networks and biological pathway features: A dual-branch deep learning approach

Shuang Li, Quanzhong Yang, Feifei Shen, Wei Chen, Shuya Zhang, Xinyi Dong and Weikai Zhang

PLOS ONE, 2026, vol. 21, issue 8, 1-19

Abstract: Drug sensitivity prediction is an important issue within the precision medicine field. IC50, which is the molar drug dose needed to decrease the viability of cells by half compared to the drug-free control, is the main pharmacodynamics parameter used for drug sensitivity analysis in large-scale pharmacogenomics screenings. Computational estimation of IC50s based on molecular and genomic factors significantly reduces costs associated with experiments for measuring cell viability and allows for accelerating the process of drug discovery. Traditional methods of IC50 calculation do not allow integrating the three-dimensional chemical structure of drugs and the biological context of particular cell lines, resulting in suboptimal model performance when using different pharmacogenomics data sources. In this work, we propose an innovative dual-branch approach based on Graph Isomorphism Network (GIN) drug representations coupled with a Multilayer Perceptron (MLP) for 50-dimensional ssGSEA pathway activities calculated from CCLE gene expression. After training on cell-line-drug pair combinations from the Genomics of Drug Sensitivity in Cancer 2 (GDSC2) dataset across various cancers, the proposed GIN+Pathway MLP model attains an R2 of 0.8553 and a Pearson Correlation Coefficient (PCC) of 0.9249 on the testing split of the same dataset. In a variant ablation study of six variants, we find that eliminating the pathway MLP component lowers the R2 value by more than 0.15, thus proving the importance of biological features in the two-branch model. The performance of our proposed model exceeds benchmark scores for models such as GraphDRP (PCC = 0.870, R2 = 0.756) and DeepCDR (PCC = 0.847, R2 = 0.720) when tested on the same GDSC2 dataset.

Date: 2026
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0354669

DOI: 10.1371/journal.pone.0354669

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