WRN helicase is a synthetic lethal target in microsatellite unstable cancers

Chan, Edmond M.; Shibue, Tsukasa; McFarland, James M.; Gaeta, Benjamin; Ghandi, Mahmoud; Dumont, Nancy; González, Alfredo; McPartlan, Justine S.; Li, Tianxia; Zhang, Yanxi; Liu, Jie Bin; Lazaro, Jean-Bernard; Gu, Peili; Piett, Cortt G.; Apffel, Annie; Ali, Syed O.; Deasy, Rebecca; Keskula, Paula; Ng, Raymond W.S.; Roberts, Emma A.; Reznichenko, Elizaveta; Leung, Lisa; Alimova, Maria; Schenone, Monica; Islam, Mirazul; Maruvka, Yosef E.; Liu, Yang; Roper, Jatin; Raghavan, Srivatsan; Giannakis, Marios; Tseng, Yuen-Yi; Nagel, Zachary D.; D’Andrea, Alan D.; Root, David E.; Boehm, Jesse S.; Getz, Gad; Chang, Sandy; Golub, Todd R.; Tsherniak, Aviad; Vázquez, Francisca; Bass, Adam J.

doi:10.1038/s41586-019-1102-x

Cited by 298 publications

(216 citation statements)

References 46 publications

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“…We have exploited our XL collection to assess if WRN dependency, which has been recently reported as a new synthetic lethality trait in MSI-H cancers (51)(52)(53)(54), could also apply to MSI-like colorectal tumors. MSI-like CRC models are genetically MSS, but bear intrinsic transcriptional features that resemble MSI-H cancers (55).…”

Section: Discussionmentioning

confidence: 99%

Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer

Lazzari

Corti

Picco

et al. 2019

Clinical Cancer Research

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Section: Discussionmentioning

confidence: 99%

Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer

Lazzari

Corti

Picco

et al. 2019

Clinical Cancer Research

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“…Extensive screening of cancer cell lines has been performed under the DepMap and Project Score initiatives to identify context-specific weaknesses and cancer biomarkers. Analyses of this data 215 have revealed activation of oncogenic pathways and oncogene dependencies (Tsherniak et al, 2017) as well as biomarker type dependencies such as Werner helicase, WRN, in colorectal and ovarian cell lines with MSI (Behan et al, 2019;Chan et al, 2019). However, despite these efforts, questions about what might be systematically missing from these data have, to our knowledge, not been rigorously explored.…”

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confidence: 99%

Multiplex enCas12a screens show functional buffering by paralogs is systematically absent from genome-wide CRISPR/Cas9 knockout screens

Dede

McLaughlin

Hart³

2020

Preprint

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Major efforts on pooled library CRISPR knockout screening across hundreds of cell lines have identified genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the number of essential genes detected from these monogenic knockout screens are very low compared to the number of constitutively expressed genes in a cell, raising 5 the question of why there are so few essential genes. Through a systematic analysis of screen data in cancer cell lines generated by the Cancer Dependency Map, we observed that half of all constitutively-expressed genes are never hits in any CRISPR screen, and that these neveressentials are highly enriched for paralogs. We investigated paralog buffering through systematic dual-gene CRISPR knockout screening by testing algorithmically defined ~400 candidate paralog 10 pairs with the enCas12a multiplex knockout system in three cell lines. We observed 24 synthetic lethal paralog pairs which have escaped detection by monogenic knockout screens at stringent thresholds. Nineteen of 24 (79%) synthetic lethal interactions were present in at least two out of three cell lines and 14 of 24 (58%) were present in all three cell lines tested, including alternate subunits of stable protein complexes as well as functionally redundant enzymes. Together these 15 observations strongly suggest that paralogs represent a targetable set of genetic dependencies that are systematically under-represented among cell-essential genes due to genetic buffering in monogenic CRISPR-based mammalian functional genomics approaches. 20 through immense monogenic screening efforts, multiple groups revealed lists of ~2000 highly concordant human essential genes, and comparison of CRISPR technology to orthogonal techniques such as random insertion of gene traps also showed consistent results (Blomen et al., 2015; Hart et al., 2015; Wang et al., 2015).

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“…PARP-1, a major member of PARP family, plays an important role in a variety of biological functions, including DNA repair, genomic stability, and gene expression (Gibson et al, 2016). PARP-1 inhibitor has been approved for clinical treatments for several tumors, such as ovarian cancers (Lin and Kraus, 2017), microsatellite unstable cancers (Chan et al, 2019) and pancreatic cancers (Tuli et al, 2019), with satisfactory clinical effects and safety. Interestingly, the potential of PARP-1 inhibitor in nontumor diseases has been put forward by some researchers and clinical physicians, especially in the scope of CNS diseases.…”

Section: Discussionmentioning

confidence: 99%

Delayed PARP-1 Inhibition Alleviates Post-stroke Inflammation in Male Versus Female Mice: Differences and Similarities

Chen

et al. 2020

Front. Cell. Neurosci.

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Post-stroke inflammation is almost involved in the whole process of stroke pathogenesis, which serves as a prime target for developing new stroke therapies. Despite known sex differences in the incidence and outcome of stroke, few preclinical or clinical studies take into account sex bias in treatment. Recent evidence suggests that poly (ADP-ribose) polymerase (PARP)-1 inhibitor exerts sex-specific neuroprotection in the ischemic stroke. This study was aimed to investigate the effects of delayed PARP-1 inhibition on post-stroke inflammation and possible sexual dimorphism, and explore the possible relevant mediators. In male and female C57BL/6 mice subjected to transit middle cerebral artery occlusion (MCAO), we found that delayed treatment of PARP-1 inhibitor at 48 h following reperfusion could comparably alleviate neuro-inflammation at 72 h after stroke. Whereas, more remarkable reduction of iNOS and MMP9 induced by PARP-1 inhibition were found in male MCAO mice, and the improvement of behavioral outcomes was more prominent in male MCAO mice. In addition, we further identified that PARP-1 inhibitor might equivalently suppress microglial activation in males and females in vivo and in vitro. With proteomic analysis and western blotting assay, it was found that stroke-induced peroxiredoxin-1 (Prx1) expression was significantly affected by PARP-1 inhibition. Interestingly, injection of recombinant Prx1 into the ischemic core could block the anti-inflammatory effects of PARP-1 inhibitor in the experimental stroke. These findings suggest that PARP-1 inhibitor has effects on regulating microglial activation and post-stroke inflammation in males and females, and holds promise as a novel therapeutic agent for stroke with extended therapeutic time window. Efforts need to be made to delineate the actions of PARP-1 inhibition in stroke, and here we propose that Prx1 might be a critical mediator.

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WRN helicase is a synthetic lethal target in microsatellite unstable cancers

Cited by 298 publications

References 46 publications

Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer

Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer

Multiplex enCas12a screens show functional buffering by paralogs is systematically absent from genome-wide CRISPR/Cas9 knockout screens

Delayed PARP-1 Inhibition Alleviates Post-stroke Inflammation in Male Versus Female Mice: Differences and Similarities

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