Personalized Cancer Therapy Prioritization Based on Driver Alteration Co-occurrence Patterns

Identification of actionable genomic vulnerabilities is the cornerstone of precision oncology. Based on a large-scale drug screening in patient derived-xenografts, we uncover connections between driver gene alterations, derive Driver Co-Occurrence (DCO) networks, and relate these to drug sensitivity. Our collection of 53 drug response predictors attained an average balanced accuracy of 58% in a cross-validation setting, which rose to a 66% for the subset of high-confidence predictions. Morevover, we experimentally validated 12 out of 14 de novo predictions in mice. Finally, we adapted our strategy to obtain drug-response models from patients’ progression free survival data. By revealing unexpected links between oncogenic alterations, our strategy can increase the clinical impact of genomic profiling.