Abstract Background Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient’s response to a variety of therapies in multiple cancer types, without training on previous treatment response data. We study ENLIGHT in two translationally oriented scenarios: Personalized Oncology (PO) , aimed at prioritizing treatments for a single patient, and Clinical Trial Design (CTD ), selecting the most likely responders in a patient cohort. Findings Evaluating ENLIGHT’s performance on 21 blinded clinical trial datasets in the PO setting, we show that it can effectively predict a patient’s treatment response across multiple therapies and cancer types. Its prediction accuracy is better than previously published transcriptomics-based signatures and is comparable to that of supervised predictors developed for specific indications and drugs. In combination with the IFN-γsignature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, ENLIGHT can potentially enhance clinical trial success for immunotherapies and other monoclonal antibodies by excluding non-responders, while overall achieving more than 90% of the response rate attainable under an optimal exclusion strategy. Conclusion ENLIGHT demonstrably enhances the ability to predict therapeutic response across multiple cancer types from the bulk tumor transcriptome. Funding This research was supported in part by the Intramural Research Program, NIH and by the Israeli Innovation Authority.

Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome