Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells

Abstract

34Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By 35 leveraging recent large-scale genomic profiling and functional screening of cancer cell lines we 36 identified Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite 37 instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair is frequently 38 detected in human malignancies, in particular in colorectal, endometrial and gastric cancers. We 39 demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite 40 stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in 41

Microsatellite instability: A 2024 update

“…Four research groups independently determined, through the use of distinct functional screening techniques, that MSI-H malignancies rely on the WRN helicase to maintain genome stability and ensure cellular survival. [30][31][32][33][34] Expanded TA-dinucleotide repeats were identified as prevalent sites of DNA breakage in MSI cancer cells when WRN was deficient. 35 These findings uncovered the mechanism underlying the synthetic lethality that exists between MSI and WRN deficiency and identified a novel biomarker for MSI (Figure 4).…”