Alejandro Álvarez Quilón - CRISPR and Base Editing Genetic Screens Enable the Discovery and Validation of Drug Targets for Precision Oncology

The focus of precision oncology over the last 25 years has been on targeting druggable oncogenes with gain-of-function genetic alterations (i.e., BCR-ABL and EGFR). However, most solid tumors do not carry these types of mutations, but instead alterations in undruggable oncogenes or loss-of-function mutations in tumor suppressors. Synthetic lethality is a concept in which the simultaneous targeting of two pathways results in cell death, whereas the targeting of either pathway alone does not. In precision oncology, synthetic lethality can be exploited to kill tumor cells carrying specific genetic lesions, when combined with pharmacological inhibition of a synthetic lethal pair. Following this approach, several poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of homologous recombination-deficient (HRD) cancers, clinically validating the concept of synthetic lethality. At the meeting, I will showcase a series of examples on how Repare Therapeutics SNIPRx® functional genomic platform leverages CRISPR- and Base Editing- enabled screening to support precision oncology, from early target identification to the clinic. First, I will present the identification and genetic validation of three synthetic lethal targets for HRD and CCNE1-amplified tumors. Next, I will present a series of CRISPR chemical genetic screens that identified additional patient selection biomarkers for several small molecule inhibitors we developed for these validated targets. Last, I will show how base editing-enabled screening can be successfully applied to two key steps in precision oncology, the identification of tractable domains in novel synthetic lethal targets, and the functional classification of variants of unknown significance (VUSs) in genetic lesions of interest. In conclusion, CRISPR genetic screens are a powerful tool in precision oncology, supporting target identification, validation, and expansion of predictive sensitivity biomarkers.