Identification of phenocopies improves prediction of targeted therapy response over DNA mutations alone

DNA mutations in specific genes can confer preferential benefit from drugs targeting those genes. However, other molecular perturbations can phenocopy pathogenic mutations, but would not be identified using standard clinical sequencing, leading to missed opportunities for other patients to benefit from targeted treatments. We hypothesized that RNA phenocopy signatures of key cancer driver gene mutations could improve our ability to predict response to targeted therapies, despite not being directly trained on drug response. To test this, we built gene expression signatures in tissue samples for specific mutations and found that phenocopy signatures broadly increased accuracy of drug response predictions in-vitro compared to DNA mutation alone, and identified additional cancer cell lines that respond well with a positive/negative predictive value on par or better than DNA mutations. We further validated our results across four clinical cohorts. Our results suggest that routine RNA sequencing of tumors to identify phenocopies in addition to standard targeted DNA sequencing would improve our ability to accurately select patients for targeted therapies in the clinic.

Automated summary

By using RNA phenocopy signatures of key cancer driver gene mutations, this study demonstrates an improved ability to predict response to targeted therapies. The phenocopy signatures were found to increase the accuracy of drug response predictions and identify additional cancer cell lines that respond well to targeted treatments. The results suggest the importance of routine RNA sequencing in addition to standard DNA sequencing for selecting patients for targeted therapies.