The Werner syndrome RECQ helicase as a therapeutic target: new insights

The WRN gene is mutated in Werner syndrome (WS), a heritable premature aging and cancer predisposition syndrome. Recent work identified WRN as a therapeutic target in a subset of cancers, emphasizing the need to better understand physiologic and cancer-specific roles for WRN that can be leveraged in therapy.

We discuss WRN as a caretaker of the genome that can function as a tumor suppressor or tumor enabler, and review progress on targeting functional WRN in microsatellite-unstable (MSI) cancers. We discuss mechanisms and distinct properties of synthetic lethality between the loss of WRN and the MSI-high tumor status, and derive lessons that can be used to identify or improve upon other cases of WRN synthetic lethality. We highlight the properties of a new generation of WRN helicase inhibitors that may confer increased lethality to MSI cancer cells while sparing normal tissues. We also discuss targeting mutant WRN in Werner syndrome and in cancer.

Significant gaps remain in understanding how WRN loss promotes pathogenesis. Filling these conceptual and informational gaps will allow better prediction of tissue-specific adverse effects of WRN helicase inhibition or WRN loss. We highlight important, unanswered questions in WRN biology and newly emerging research and translational opportunities.