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WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI)

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Targeting the DNA Damage Response for Cancer Therapy

Part of the book series: Cancer Treatment and Research ((CTAR,volume 186))

Abstract

Microsatellite instability (MSI), a type of genetic hypermutability arising from impaired DNA mismatch repair (MMR), is observed in approximately 3% of all cancers. Preclinical work has identified the RecQ helicase WRN as a promising synthetic lethal target for patients with MSI cancers. WRN depletion substantially impairs the viability of MSI, but not microsatellite stable (MSS), cells. Experimental evidence suggests that this synthetic lethal phenotype is driven by numerous TA dinucleotide repeats that undergo expansion mutations in the setting of long-standing MMR deficiency. The lengthening of TA repeats increases their propensity to form secondary DNA structures that require WRN to resolve. In the absence of WRN helicase activity, these unresolved DNA secondary structures stall DNA replication forks and induce catastrophic DNA damage.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Oncology, Columbia University, New York, USA

    Edmond M. Chan

  2. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, USA

    Edmond M. Chan

  3. Broad Institute of MIT and Harvard, Cambridge, USA

    Edmond M. Chan

  4. New York Genome Center, New York, USA

    Edmond M. Chan

  5. University of California, San Francisco, USA

    Kyla J. Foster

  6. Novartis Institutes for BioMedical Research, Cambridge, USA

    Adam J. Bass

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Correspondence to Edmond M. Chan .

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  1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Timothy A. Yap

  2. Dana-Farber Cancer Institute, Boston, MA, USA

    Geoffrey I. Shapiro

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Chan, E.M., Foster, K.J., Bass, A.J. (2023). WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI). In: Yap, T.A., Shapiro, G.I. (eds) Targeting the DNA Damage Response for Cancer Therapy. Cancer Treatment and Research, vol 186. Springer, Cham. https://doi.org/10.1007/978-3-031-30065-3_17

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  • DOI: https://doi.org/10.1007/978-3-031-30065-3_17

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  • Online ISBN: 978-3-031-30065-3

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