Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q

Neggers, Jasper E.; Paolella, Brenton R.; Asfaw, Adhana; Rothberg, Michael; Skipper, Thomas A.; Yang, Annan; Kalekar, Radha L.; Krill-Burger, John M.; Dharia, Neekesh V.; Kugener, Guillaume; Kalfon, Jérémie; Yuan, Chen; Dumont, Nancy; González, Alfredo; Abdusamad, Mai; Li, Yvonne Y.; Wu, Westley W.; Durbin, Adam D.; Wolpin, Brian M.; Piccioni, Federica; Root, David E.; Boehm, Jesse S.; Cherniack, Andrew D.; Tsherniak, Aviad; Hong, Andrew L.; Hahn, William C.; Stegmaier, Kimberly; Golub, Todd R.; Vázquez, Francisca; Aguirre, Andrew J.

doi:10.1016/j.celrep.2020.108493

Cited by 38 publications

(31 citation statements)

References 80 publications

(129 reference statements)

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“…Some synthetic lethal paralog pairs, including SEC24A/ SEC24B, COQ10A/COQ10B, CNOT7/CNOT8, TIA/TIAL, and VPS4/VPS4B, have been highlighted in previous studies (Dede et al, 2020;Gonatopoulos-Pournatzis et al, 2020;Lord et al, 2020;Neggers et al, 2020;Szyma nska et al, 2020). However, to our knowledge, many of the synthetic lethal paralogs identified in the pgPEN screens were not previously known to be functionally redundant in human cells.…”

Section: Direct Identification Of Paralog Gis In Human Lung Cancer Cellsmentioning

confidence: 83%

Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome

et al. 2021

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Section: Direct Identification Of Paralog Gis In Human Lung Cancer Cellsmentioning

confidence: 83%

Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome

et al. 2021

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“…In addition, PaCT also identified several paralog dependencies that have recently been described, including SMARCA2-SMARCA4 or SLC25A28-SLC25A37 19 . We used CRISPR GFP-depletion assays to experimentally validate the genetic dependencies on FAM50A in cells where FAM50B expression is low, and on VPS4A in VPS4B -low cell lines (Figure 3c,d and Supplementary Figure 3g,h), two paralog interactions that have recently been functionally characterized 19,52,53 .…”

Section: Resultsmentioning

confidence: 99%

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

Köferle

Schlattl

Hörmann

et al. 2021

Preprint

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Genetic networks are characterized by extensive buffering. During tumour evolution, disruption of these functional redundancies can create de novo vulnerabilities that are specific to cancer cells. In this regard, paralog genes are of particular interest, as the loss of one paralog gene can render tumour cells dependent on a remaining paralog. To systematically identify cancer-relevant paralog dependencies, we searched for candidate dependencies using CRISPR screens and publicly available loss-of-function datasets. Our analysis revealed >2,000 potential candidate dependencies, several of which were subsequently experimentally validated. We provide evidence that DNAJC15-DNAJC19, FAM50A-FAM50B and RPP25-RPP25L are novel cancer relevant paralog dependencies. Importantly, our analysis also revealed unexpected redundancies between sex chromosome genes. We show that chrX- and chrY- encoded paralogs, as exemplified by ZFX-ZFY, DDX3X-DDX3Y and EIF1AX-EIF1AY, are functionally linked so that tumour cell lines from male patients with Y-chromosome loss become exquisitely dependent on the chrX-encoded gene. We therefore propose genetic redundancies between chrX- and chrY- encoded paralogs as a general therapeutic strategy for human tumours that have lost the Y-chromosome.

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“…When 16q or 18q deletions occur separately, there is no effect on tumour growth. However, when VPS4B is inhibited in tumour cells with 16q deletion, or when VPS4A is inhibited in tumour cells with 18q deletion, synthetic lethality occurs and there is cell death (Neggers et al, 2020). Oncogenic addiction is depicted on the right, using BRAF as an example.…”

Section: Rnai and Crispr Screensmentioning

confidence: 99%

Functional genomics approaches to improve pre‐clinical drug screening and biomarker discovery

Nguyen

Caldas

2021

EMBO Mol Med

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Advances in sequencing technology have enabled the genomic and transcriptomic characterization of human malignancies with unprecedented detail. However, this wealth of information has been slow to translate into clinically meaningful outcomes. Different models to study human cancers have been established and extensively characterized. Using these models, functional genomic screens and pre-clinical drug screening platforms have identified genetic dependencies that can be exploited with drug therapy. These genetic dependencies can also be used as biomarkers to predict response to treatment. For many cancers, the identification of such biomarkers remains elusive. In this review, we discuss the development and characterization of models used to study human cancers, RNA interference and CRISPR screens to identify genetic dependencies, large-scale pharmacogenomics studies and drug screening approaches to improve pre-clinical drug screening and biomarker discovery.

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Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q

Cited by 38 publications

References 80 publications

Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome

Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

Functional genomics approaches to improve pre‐clinical drug screening and biomarker discovery

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