We are now in an era of molecular medicine, where specific
DNA alterations can be used to identify patients who will respond to specific drugs. However, there are only a handful of clinically used predictive
biomarkers in oncology. Herein, we describe an approach utilizing in vitro
DNA and
RNA sequencing and drug response data to create TreAtment Response Generalized Elastic-neT Signatures (TARGETS). We trained TARGETS drug response models using Elastic-Net regression in the publicly available Genomics of Drug Sensitivity in
Cancer (GDSC) database. Models were then validated on additional in-vitro data from the
Cancer Cell Line Encyclopedia (CCLE), and on clinical samples from The
Cancer Genome Atlas (TCGA) and Stand Up to
Cancer/Prostate Cancer Foundation West Coast
Prostate Cancer Dream Team (WCDT). First, we demonstrated that all TARGETS models successfully predicted treatment response in the separate in-vitro CCLE treatment response dataset. Next, we evaluated all FDA-approved
biomarker-based
cancer drug indications in TCGA and demonstrated that TARGETS predictions were concordant with established clinical indications. Finally, we performed independent clinical validation in the WCDT and found that the TARGETS AR signaling inhibitors (ARSI) signature successfully predicted clinical treatment response in metastatic
castration-resistant
prostate cancer with a statistically significant interaction between the TARGETS score and PSA response (p = 0.0252). TARGETS represents a pan-
cancer, platform-independent approach to predict response to oncologic
therapies and could be used as a tool to better select patients for existing
therapies as well as identify new indications for testing in prospective clinical trials.