Synthetic lethality and context-selective DNA-damage response dependencies: from genetic vulnerability to pharmacological translation.

Synthetic lethality has established DNA-damage response (DDR) dependencies as a major strategy for precision cancer therapy, exemplified by targeting BRCA1/2 and poly(ADP-ribose) polymerase (PARP). However, genetic dependency alone does not ensure pharmacological tractability or clinical utility. Emerging targets, including WRN, POLQ, USP1 and PARG, impose distinct requirements for ligandability, selectivity, target engagement, patient selection and the therapeutic window. A comparison of their structural biology, inhibitor chemotypes, SAR, pharmacodynamic strategies, resistance mechanisms and clinical development shows that successful translation requires matching a tumor-selective dependency to an experimentally validated, exposure-controllable pharmacological mechanism. This framework supports the rational prioritization of context-selective DDR dependencies beyond BRCA-PARP.