Novel Synthetic Lethal Therapeutic Strategies in Precision Oncology

Synthetic lethality is a genetic phenomenon in which the simultaneous presence of two different genetic alterations impairs cellular viability, whereas a single gene defect is compatible with cellular survival. Importantly, targeting such synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be previously considered undruggable. Various hallmarks of cancer have proven to be targetable using a synthetic lethal approach, including the DNA damage response (DDR), epigenetic alterations, and changes in cellular metabolism and proliferation. The development of high-throughput drug and CRISPR-Cas9 screening technologies has led to the discovery of new druggable synthetic lethal vulnerabilities in cell lines and to the development of novel drugs designed to target these interactions, together with associated predictive biomarkers of response capable of guiding patient selection in the clinic. Clinically approved PARP inhibitors have provided proof of concept for the synthetic lethality approach by achieving successful outcomes in patients with BRCA-mutant cancers. This has led to the discovery and development of novel synthetic lethal strategies, including novel agents targeting multiple DDR pathways and epigenetic alterations. These approaches are currently in late preclinical and/or early clinical testing. In this article, we detail emerging therapeutic strategies for synthetic lethal drug development and discuss promising therapeutic strategies targeting such interactions. These include MTA-cooperative PRMT5 inhibitors and MAT2A inhibitors in MTAP-deficient cancers, WRN inhibitors in microsatellite instablility-high tumors, as well as PKMYT1 inhibitors and WEE1 inhibitors in CCNE1-amplified tumors.