Pharmacogenomic discovery of genetically targeted cancer therapies optimized against clinical outcomes

Abstract

ABSTRACTDespite the clinical success of dozens of genetically targeted cancer therapies, the vast majority of patients with tumors caused by loss-of-function (LoF) mutations do not have access to these treatments. This is primarily due to the challenge of developing a drug that treats a disease caused by the absence of a protein target. The success of PARP inhibitors has solidified synthetic lethality (SL) as a means to overcome this obstacle. Recent mapping of SL networks using pooled CRISPR-Cas9 screens is a promising approach for expanding this concept to treating cancers driven by additional LoF drivers. In practice, however, translating signals from cell lines, where these screens are typically conducted, to patient outcomes remains a challenge. We developed a pharmacogemic (PGx) approach called “Clinically Optimized Driver Associated PGx” (CODA-PGx) that accurately predicts genetically targeted therapies with clinical-stage efficacy in specific LoF driver contexts. Using approved targeted therapies and cancer drugs with available real-world evidence and molecular data from hundreds of patients, we discovered and optimized the key screening principles predictive of efficacy and overall patient survival. In addition to establishing basic technical conventions, such as drug concentration and screening kinetics, we found that replicating the driver perturbation in the right context, as well as selecting patients where those drivers are genuine founder mutations, were key to accurate translation. We used CODA-PGX to screen a diverse collection of clinical stage drugs and report dozens of novel LoF genetically targeted opportunities; many validated in xenografts and by real-world evidence. Notable examples include treating STAG2-mutant tumors with Carboplatin, SMARCB1-mutant tumors with Oxaliplatin, and TP53BP1-mutant tumors with Etoposide or Bleomycin.One Sentence SummaryWe identified principles of pharmacogenomic screening that predict clinical efficacy in cancer patients with specific driver mutations.