Whole exome precision oncology targeting synthetic lethal vulnerabilities across the tumor transcriptome

Precision oncology has made significant advances in the last few years, mainly by targeting actionable mutations in cancer driver genes. However, the proportion of patients whose tumors can be targeted therapeutically remains limited. Recent studies have begun to explore the benefit of analyzing tumor transcriptomics data to guide patient treatment, raising the need for new approaches for systematically accomplishing that. Here we show that computationally derived genetic interactions can successfully predict patient response. Assembling a broad repertoire of 32 datasets spanning more than 1,500 patients and including both tumor transcriptomics and response data, we predicted the response in 17 out of 21 targeted and 8 out of 11 checkpoint therapy datasets across 8 different cancer types with considerable accuracy, without ever training on these datasets. Analyzing the recently published multi-arm WINTHER trial, we show that the fraction of patients benefitting from transcriptomic-based treatments could potentially be markedly increased from 15% to about 85% by targeting synthetic lethal vulnerabilities in their tumors. In summary, this is the first computational approach to obtain considerable predictive performance across many different targeted and immunotherapy datasets, providing a promising new way for guiding cancer treatment based on the tumor transcriptomics of cancer patients.