Signalling pathway research helps discover a new drug target for aggressive eye cancer

Key points:

• Scientists from the Wellcome Sanger Institute and collaborators, including cell signalling experts at the Institute, have identified a new therapeutic target for the treatment of metastatic eye melanoma, an aggressive and difficult to treat eye cancer.
• The group at the Sanger used a genetic screen to identify a clear vulnerability in uveal melanoma cells when a protein called CDS2 is lost.
• The key discovery focuses on the genes CDS1 and CDS2, which work together in a way that has not been shown before. Both genes encode enzymes that are involved in phosphoinositide synthesis, which is essential in key cancer pathways including melanoma.
• Previous research from the Institute has described the loss of CDS2 in genetically engineered mouse cells and characterised its effect on phosphoinositide synthesis.
• It is hoped this latest research will stimulate efforts to target CDS2 in uveal melanoma and other tumour types with very low levels of CDS1.

A paper published today by researchers from the Wellcome Sanger Institute and their collaborators (Chan et al.,) identifies a protein called CDS2 as a novel drug target with therapeutic potential for metastatic eye (uveal) melanoma — an aggressive eye cancer — with implications for a range of other cancers.

The research aimed to identify essential genes for cell survival in human eye melanoma cell lines in order to develop more effective treatments.

Uveal melanoma is a rare but deadly cancer with up to 600 patients diagnosed each year across the UK.¹ Treatment options are invasive but generally successful, however approximately half of all patients go on to develop metastatic disease in the liver within two to three years.^2,3

The research led by the group of Dr David Adams at the Sanger Institute involved CRISPR-Cas9 gene editing to knock out — or ‘turn off’ — genes individually and in pairs to look for lethal genetic interactions, also known as synthetic lethal pairs, in 10 human uveal melanoma cell lines.

Amongst the 76 genes identified that individually are essential to uveal melanoma and 105 gene pairs that interact lethally when disrupted together, the approach highlighted a particular importance for the interaction between genes called CDS2 and CDS1. CDS2 usually works with CDS1, a closely related enzyme, to provide a robust route for the synthesis of a group of phospholipids called ‘phosphoinositides’, which are essential for many cell functions, including cancer cell growth.

The researchers discovered that uveal cancer cells, which show low expression of CDS1, are highly dependent on CDS2 for survival.

Dr Jenny Pui Ying Chan, first author formerly at the Wellcome Sanger Institute and now Clinical Research Fellow at the Royal Marsden Hospital, said: “By uncovering specific genetic vulnerabilities like the CDS1 and CDS2 relationship, we’re opening the door to new therapies that could one day lead to more effective treatments for patients.”

With most healthy cells having significant CDS1 expression, targeting CDS2 may be able to kill the uveal melanoma cancer cells, while sparing normal healthy cells. This approach also holds promise for several other cancer types in which CDS1 expression is known to be particularly low.

Dr David Adams, senior author and Group Leader at the Wellcome Sanger Institute, said: “Our study reveals a previously unrecognised genetic relationship in uveal melanoma, driven by a particular relationship between the CDS1 and CDS2 genes. This discovery not only deepens our understanding of tumour biology but also opens new routes for precise therapy development. What makes this finding especially exciting is its relevance beyond uveal melanoma as our research suggests a therapeutic potential for a broad range of cancers.”

Previous work from the Institute (Collins et al., 2024) shows loss of CDS2 is critical to sustain the increased demand for phosphoinositides after hormone-driven cell stimulation (via the G protein-coupled receptor-phospholipase C pathway). Uveal cancers have activating mutations in the G-protein-PLC pathway that drive increased phosphoinositide synthesis, providing a clear rationale for why these cancers may be especially vulnerable to loss of CDS2. In the melanoma lines analysed as part of the collaboration with the Adam’s group, Institute researchers showed that loss of CDS2 causes a massive re-routing of metabolism away from synthesis of phosphoinositides into lipid droplets (shown in the main figure).

Dr Phill Hawkins, former group leader and now honorary group leader at the Babraham Institute, said: “It’s tremendously exciting to see this work from the Sanger identifying CDS2 as a potential target for cancer treatment. It is a lovely example of how core signalling research funded by the BBSRC over many years has provided the rationale for a new therapeutic approach to treating these aggressive diseases.”

Dr Anna Kinsella, Research Information Manager at Cancer Research UK, said: “We need better options to treat uveal melanoma. To make progress, it’s vital for researchers to understand more about the disease on a molecular level. That’s why it’s promising to see the results of this work, uncovering detailed elements of the biology behind the disease and opening up new opportunities to beat it. This discovery could now pave the way to new, targeted treatments in the future, not just for uveal melanoma, but also for other cancer types."

Notes to Editors

This news item is adapted from a press release from the Wellcome Sanger Institute: New drug target for aggressive eye cancer discovered.

Text references:

1. Melanoma UK. Ocular Melanoma. Available at: https://www.melanomauk.org.uk/ocular-melanoma- om#:~:text=Also%20known%20as%20Uveal%20melanoma,who%20also%20offer%20support%20services. [Last accessed: June 2025]
2. Kaštelan, S. et al. (2022). Liver metastasis in uveal melanoma - treatment options and clinical outcome. Front. Biosci. (Landmark Ed). doi: 10.31083/j.fbl2702072.
3. The only treatment approved by the National Institute for Health and Care Excellence (NICE) in the UK is tebentafusp, which helps the immune system recognise and attack melanoma cells. It is approved for metastatic uveal melanoma in patients only with a specific genetic marker known as HLA-A*02:01, which plays an important role in how the body responds to foreign substances.

Publication reference

Pui Ying Chan et al. (2025) ‘The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability across multiple tumor types.’ Nature Genetics.

Press contact

For the Wellcome Sanger Institute: Susannah Young , Press Office, Wellcome Sanger Institute, 07907391759, press.office@sanger.ac.uk

At the Babraham Institute: Dr Louisa Wood, Head of Communications, louisa.wood@babraham.ac.uk

Image description

Uveal melanoma cells showing the accumulation of lipid droplets in the absence of CDS2 (right), compared with cells with functional CDS2 (left). Lipid droplets are stained green with BODIPY™ 493/503. Image from Chen et al., Nature Genetics.

Affiliated authors (in author order):

David Barneda, former postdoctoral fellow, Hawkins-Stephens lab

Phillip Hawkins, honorary group leader

Len Stephens, honorary group leader

Research funding

This research is part-funded by Wellcome, the Medical Research Council and Cancer Research UK. A full list of funders can be found in the acknowledgements in the publication.