Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation

Targeting synthetic lethal interactions has emerged as a promising strategy for cancer therapeutics, particularly by exploiting DNA damage response (DDR) pathways. A well-known example of this are PARP inhibitors, that selectively kill cancer cells compromised by mutations in DDR genes like BRCA1/2, while sparing normal cells with functional homologous recombination repair. These compounds have substantially improved clinical outcomes, especially in BRCA1/2-mutated ovarian cancer, enhancing both survival rates and quality of life. Their great clinical impact has been constrained by the appearance of resistance and safety concerns. New generation PARP inhibitors are being developed with enhanced selectivity and reduced side effects. Beyond PARP inhibition, several other drugs inhibiting key DDR components, such as ATR, ATM and DNA-PK, have progressed to clinical trials. These DDR inhibitors are being studied alone or in combination with chemotherapy, radiotherapy, immunotherapy or other targeted therapy, increasing efficacy and improving outcomes in resistant and advanced cancers. While most synthetic lethality-based clinical trials in oncology target DDR, an increasing trend in the preclinical and clinical setting is focused on inhibiting non-DDR pathways (e.g., PRMT5 and SMARCA4/2). However, challenges remain in determining the most effective combinations, identifying which patient populations will benefit the most from these therapies and overcoming resistance. Continued research is also essential to fully understand the intricate network of synthetic lethality and maximize the therapeutic potential of synthetic lethality-based therapies. Nonetheless, targeting synthetic lethal interactions with inhibitors represents an exciting frontier in precision oncology, offering the potential for more tailored, effective and less toxic cancer treatments.