Abstract 946: A silver jubilee for synthetic lethality in cancer treatment: where do we stand

Abstract

Background: Synthetic lethality (SL) denotes a genetic interaction between two genes whose co-inactivation is detrimental to cells. Since the seminal paper of Hartwell and colleagues has raised the possibility that SL can be used to devise highly selective cancer treatments, it has been one of the promising approaches for precision oncology and drug discovery. Many different avenues have so far been explored to bring this idea to the clinic. As 25 years have passed by now, we take stock and systematically and comprehensively chart the landscape of SL-based preclinical research and clinical trials. Approach and Key Findings: We systematically mined both public and commercial databases to curate the preclinical and clinical landscape of the SL-based oncology studies. Our analysis shows that the number of SL oncology studies is rapidly growing since the first identification of the well-known BRCA-PARP synthetic lethality axis. Importantly, we find that the success rate of SL oncology trials is significantly higher than non-SL-based trials. While more than 70% of SL-oncology trials involve genes in the most-studied DNA damage response (DDR) pathways, the fraction of SL trials involving non-DDR pathways keeps growing since 2009. We further charted the landscape of SL triplets, which is a promising future higher-order extension of the conventional pairwise SL interactions. We find that only about 8% of preclinically validated SL triplets were clinically tested in trials, providing new opportunities for more refined clinical trial design. Our analysis suggests that emerging opportunities in SL oncology may arise from metabolic and paralogous interactions, disease-agnostic biomarkers, context-specific combinations against treatment resistance, artificial intelligence and data science approaches, and multi-omics patient stratification signatures. Significance: Taken together, our findings testify that a considerable potential benefits of SL based approaches are yet untapped, reinforcing the belief that the synthetic lethality approach may serve as a key driver of precision oncology going forward. Citation Format: Joo Sang Lee, Youngmin Chung, Ashwin V. Kammula, Alejandro A. Schaffer, Eytan Ruppin. A silver jubilee for synthetic lethality in cancer treatment: where do we stand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 946.