Sanger Institute and collaborators discover new drug target for eye cancer

Published today in Nature Genetics, scientists from the Wellcome Sanger Institute and their collaborators reveal how they used CRISPR screening — a gene-editing tool — to reveal two genes, CDS1 and CDS2, which strongly rely on each other in metastatic eye melanoma. This could pave the way for more targeted and effective cancer treatments, which are currently lacking, the researchers reveal.

The discovery advances the scientific understanding of gene targets for a range of cancers but may also provide a hopeful outlook for eye cancer patients with very limited therapeutic options.

Uveal melanoma is a rare but deadly cancer with up to 600 patients diagnosed each year across the UK. There are only four sites across the UK which treat this type of cancer. 

The treatment options for patients are invasive and include having their eye surgically removed or receiving radiation therapy to the eye. Whilst these treatments are successful and cancer recurrences in the eye rarely happen, approximately half of all patients will go on to develop metastatic disease in the liver within two to three years.

To help address the need for more alternative treatment options, scientists from the Sanger Institute and their collaborators sought to better understand the genetics of uveal melanoma cells. 

In a new study, the researchers used a gene-editing tool called CRISPR-Cas9, which enables precise changes to DNA, in order to identify single genes and gene pairs that are essential for the cancer cells to survive and grow. 

Using CRISPR-Cas9 screening in 10 human uveal melanoma cell lines, the researchers knocked out — or 'turned off'— genes individually and in pairs to look for lethal genetic interactions, also known as synthetic lethal pairs.

The researchers identified 76 genes that individually are essential to uveal melanoma and 105 gene pairs that interact lethally when disrupted together. 

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. 

The researchers discovered that cancer cells with low expression of CDS1 are highly dependent on CDS2 for survival.They showed that loss of CDS2 disrupts phosphoinositide synthesis – a type of phospholipid production.

This leads to impaired tumour growth and cell death — but only when CDS1 expression levels are low. Reintroducing CDS1 reversed these effects, confirming the dependent role of this gene pair in tumour cell survival. With many normal cells having normal CDS1 expression, a treatment strategy may be able to kill cancer cells, while sparing healthy cells. 

The researchers then looked at datasets from other types of cancers to reveal that low expression of CDS1 is seen across multiple cancer types. The researchers are now also investigating if targeting the CDS1/CDS2 interaction effectively kills cancer cells in these malignancies. 

The study therefore opens up the idea that the interaction between CDS1 and CDS2 has potential to be a therapeutic target across a range of cancers. The research is a significant stepping stone in providing a hopeful outlook for patients with rare cancers with very few treatment options. 

Dr Jenny Pui Ying Chan, first author formerly at the Wellcome Sanger Institute and now Clinical Research Fellow at The Royal Marsden NHS Foundation Trust, said: “Uveal melanoma is a rare but aggressive cancer, with very few treatments especially once it spreads to other parts of the body. 

“This research is an important first step in changing that and providing hope for future patients. 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.”

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."

Dr David Adams, senior author and Group Leader at the Wellcome Sanger Institute, added: “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.”