Gene expression has more power for predicting in vitro cancer cell vulnerabilities than genomics

Achieving precision oncology requires accurate identification of targetable cancer vulnerabilities in patients. Generally, genomic features are regarded as the state-of-the-art method for stratifying patients for targeted therapies. In this work, we conduct the first rigorous comparison of DNA- and expression-based predictive models for viability across five datasets encompassing chemical and genetic perturbations. We find that expression consistently outperforms DNA for predicting vulnerabilities, including many currently stratified by canonical DNA markers. Contrary to their perception in the literature, the most successful expression-based models depend on few features and are amenable to biological interpretation. This work points to the importance of exploring more comprehensive expression profiling in clinical settings.