Synthetic lethal target (SL target)

A synthetic lethal target refers to a gene or protein whose inhibition leads to cell death only in the context of a specific genetic alteration, typically a loss-of-function mutation in a tumor suppressor gene [1, 3]. This concept, rooted in classical genetics, allows for the selective targeting of cancer cells while sparing normal cells that lack the sensitizing mutation [4, 8]. The most prominent clinical application is the use of PARP inhibitors (e.g., Olaparib) in cancers with BRCA1 or BRCA2 mutations, where the loss of homologous recombination repair renders cells dependent on PARP-mediated DNA repair pathways [1, 10]. Beyond DNA repair, synthetic lethal targets are being identified in areas such as metabolism, including MAT2A or PRMT5 in MTAP-deleted cancers, and chromatin remodeling, such as SMARCA2 in SMARCA4-deficient cancers [7, 8, 9]. Identifying these targets often involves large-scale functional genomic screens, such as CRISPR-Cas9 or RNAi libraries, to map genetic dependencies across diverse cancer genotypes [4, 6]. While highly promising for precision oncology, challenges include the development of resistance and the need for robust biomarkers to identify patient populations that will benefit from these therapies [1, 4].

Other names

Synthetic lethality targetSL targetGenotype-selective targetConditional essentiality target

Synthetic lethality