Synthetic Lethality Strikes: Outsmarting Cancer with Precision Medicine

Dear Colleagues,

Synthetic lethality has emerged as a genetically targeted strategy in cancer treatment, offering the potential to bullseye tumor cells that carry specific genetic defects while sparing healthy cells and tissues.

Synthetic lethality exploits the vulnerabilities caused by mutations in DNA repair, including homologous recombination (HR) pathways. The concept of BRCAness as an Achilles’ heel of certain types of cancers (including breast and pancreatic cancer) has successfully prompted the use of PARP inhibitors and promising targets such as RAD51 and RAD52, which are gathering attention.

In BRCA-mutant cancer cells, HR is defective due to loss of BRCA function, causing cell death, while normal cells survive by repairing the damage. New RAD51–BRCA2 and PARP disruptor combinations simultaneously impair two DNA repair pathways, thereby triggering synthetic lethality.

This Special Issue brings together original research and critical reviews that span the discovery, validation, and therapeutic exploitation of synthetic lethality in cancer through DNA damage response (DDR) and non-DDR modulators. Emphasis is placed on new molecules that induce synthetic lethality, encompassing medicinal chemistry, mechanistic insights, clinical translation, and combinatorial approaches, unlocking new avenues in precision medicine. Contributions underscore the dynamic potential of synthetic lethality as a cornerstone in the next generation of targeted cancer therapies.

We would like to acknowledge Dr. Giovanna Panzeca  (Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy) for her participation as Guest Editor Assistant in the development of this Special Issue.

Prof. Dr. Stefania Butini
Guest Editor

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