Targeting synthetic lethality: an effective therapeutic approach in ovarian and endometrial cancers.

Synthetic lethality (SL) is a promising therapeutic concept that relies on the indirect targeting of vulnerabilities acquired through genetic mutations. Ovarian and endometrial cancers frequently exhibit mutations in the breast cancer (BRCA), phosphatase and tensin homolog (PTEN), AT-rich interactive domain-containing protein 1A (ARID1A) and TP53 genes, as well as DNA repair pathway deficiencies. Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in various cancers with BRCA mutations and homologous recombination deficiency. In addition to PARPi, there has been an expansion of drugs exploiting the selective vulnerability of cancer cells via SL, such as WEE1 kinase and Ataxia Telangiectasia and Rad3-related protein (ATR). WEE1 inhibitors have shown encouraging results in combination with chemotherapy, increasing the objective response rate in patients with platinum-resistant TP53-mutated ovarian cancer. ATR inhibitors are currently being evaluated in ARID1A-mutated tumours, with preliminary results confirming their therapeutic potential.