The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types

Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries. Among our 76 uveal melanoma-specific essential genes and 105 synthetic lethal gene pairs, we identified and validated the CDP-diacylglycerol synthase 2 gene (CDS2) as a genetic dependency in the context of low CDP-diacylglycerol synthase 1 gene (CDS1) expression. We further demonstrate that CDS1/CDS2 forms a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis and increased cellular apoptosis and that re-expression of CDS1 rescues this cell fitness defect. We extend our analysis using pan-cancer data, confirming increased CDS2 essentiality in diverse tumor types with low CDS1 expression. Thus, the CDS1/CDS2 axis is a therapeutic target across a range of cancers.

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Publication Details

Journal
Nature Genetics
Published
2025-07-01
DOI
https://doi.org/10.1038/s41588-025-02222-1
Citations
8
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
6.45

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article

The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types

Sanju Sinha, Gabriel Balmus, Fernanda Guadalupe Arriaga-González, Saamin Cheema et al.
8 citations
Nature Genetics
Ubiquitin and proteasome pathways
6.45
article

The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types

Sanju Sinha, Gabriel Balmus, Fernanda Guadalupe Arriaga-González, Saamin Cheema, Jyoti S. Choudhary, David Barneda, Kim Ping Wong, Lodewyk F.A. Wessels, Martin Del Castillo Velasco‐Herrera, Louise van der Weyden, Len Stephens, Phillip T. Hawkins, Victoria Offord, Colm J. Ryan, Zuza Kozik, Pui Ying Chan, Larissa Satiko Alcântara Sekimoto Matsuyama, Anjan Venkatesh, Sumeet Patiyal, Martha Estefania Vázquez‐Cruz, Emanuel Gonçalves, Vivek Iyer, Nicola Thompson, Michael Woods, Diana Alexander, Francesco Raimondi, Ishan Mehta, Victoria Harle, Alessandro Vinceti, Francesco Iorio, Luisa Bisceglia, Joris van de Haar, Jun Sung Park, David J. Adams, Rebeca Olvera-León
article en
8 citations

Abstract

Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries. Among our 76 uveal melanoma-specific essential genes and 105 synthetic lethal gene pairs, we identified and validated the CDP-diacylglycerol synthase 2 gene (CDS2) as a genetic dependency in the context of low CDP-diacylglycerol synthase 1 gene (CDS1) expression. We further demonstrate that CDS1/CDS2 forms a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis and increased cellular apoptosis and that re-expression of CDS1 rescues this cell fitness defect. We extend our analysis using pan-cancer data, confirming increased CDS2 essentiality in diverse tumor types with low CDS1 expression. Thus, the CDS1/CDS2 axis is a therapeutic target across a range of cancers.

Nature GeneticsVol. 57(7)
University College Dublin (IE), Instituto de Engenharia de Sistemas e Computadores Investigação e Desenvolvimento (PT), Babraham Institute (GB), University of Lisbon (PT), Institute of Cancer Research (GB), Scuola Normale Superiore (IT), Autonomous University of Queretaro (MX), University of Cambridge (GB), Wellcome Sanger Institute (GB), The Netherlands Cancer Institute (NL), Oncode Institute (NL), Human Technopole (IT), UK Dementia Research Institute (GB), National Cancer Institute (US), Romanian Institute of Science and Technology (RO), Center for Cancer Research (US), Universidad Nacional Autónoma de México (MX)
Center for Strategic Scientific Initiatives, National Cancer Institute, Wellcome Trust, Medical Research Council, Biotechnology and Biological Sciences Research Council, Fundação para a Ciência e a Tecnologia
Good health and well-being
Openalex Percentile: Top 3%
Ubiquitin and proteasome pathways
6.45
DOIOpen Access PDFOpenAlex
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