Abstract
Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data of cancer cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in severe genome integrity defects. ATP-binding deficient variants of WRN fail to rescue the viability phenotype of WRN-depleted MSI-H cancer cells. Reconstitution and depletion studies indicate that WRN dependence is not attributable to acute loss of MMR gene function but might arise during sustained MMR-deficiency. Our study suggests that pharmacological inhibition of WRN helicase function represents an opportunity to develop a novel targeted therapy for MSI-H cancers.
Highlights
Defects in components of the DNA repair machinery, such as BRCA1/2 mutations or impaired DNA mismatch repair (MMR), are a common characteristic of tumor cells, accelerating the accumulation of DNA mutations or chromosomal aberrations that are required for neoplastic growth and transformation (Kinzler and Vogelstein, 1997)
An analysis of variable importance revealed MLH1 expression as the feature most highly associated with the classification outcome, in line with the frequent inactivation of the MLH1 gene in microsatellite instability-high (MSI-H) colorectal cancer (CRC) (Cunningham et al, 1998; Herman et al, 1998; Kane et al, 1997; Kuismanen et al, 2000) (Figure 1—figure supplement 1A)
Werner syndrome helicase (WRN) dependency anti-correlates with MLH1 mRNA expression levels among the cell models used in Project DRIVE (Figure 1—figure supplement 1B; p=1.02*10À4, Fisher’s exact test, stratification of MLH1-low and -high expressing cell models according to median MLH1 expression [TPM 37.44])
Summary
Defects in components of the DNA repair machinery, such as BRCA1/2 mutations or impaired DNA mismatch repair (MMR), are a common characteristic of tumor cells, accelerating the accumulation of DNA mutations or chromosomal aberrations that are required for neoplastic growth and transformation (Kinzler and Vogelstein, 1997). MMR deficiency is caused by inactivation of genes of the DNA repair machinery involved in the resolution of nucleotide base-base mismatches during DNA replication (Jiricny, 2006; Kunkel and Erie, 2015). Werner syndrome helicase (WRN) is a member of the RecQ DNA helicase subfamily (Croteau et al, 2014; Yu et al, 1996). The critical function of this protein family in genome maintenance is underscored by the fact that defects in three of the five family members – WRN, Bloom Syndrome RecQ Like Helicase (BLM) and RecQ Like Helicase 4 (RECQL4) – give rise to human disease syndromes associated with developmental defects and cancer predisposition (Brosh, 2013; Oshima et al, 2017). By leveraging a recently defined map of cancer cell specific vulnerabilities (McDonald et al, 2017) and a comprehensive molecular characterization of cancer cell models (Barretina et al, 2012; Streit et al, 2019) we identify WRN helicase as a selective dependency in MSI-H cancer cell lines
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