CRISPR Screens Reveal Genetic Weak Spot in Metastatic Eye Cancer

New research has found a novel target with therapeutic potential for metastatic eye melanoma — an aggressive eye cancer — with implications for a range of other cancers.

Published today (4 July) in Nature Genetics, scientists from the Wellcome Sanger Institute and their collaborators 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.

This research advances the scientific understanding of gene targets for a range of cancers but also may 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.6 This leads to impaired tumour growth and cell death — but only when CDS1 expression levels are low. With many normal cells having normal CDS1 expression, this treatment strategy may be able to kill cancer cells, while sparing healthy cells. Reintroducing CDS1 reversed these effects, confirming the dependent role of this gene pair in tumour cell survival.

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 investigating if targeting the CDS1/CDS2 interaction effectively kills cancer cells in these malignancies.

Therefore, the study 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.

Reference: Chan PY, Alexander D, Mehta I, et al. The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types. Nat Genet. 2025:1-12. doi: 10.1038/s41588-025-02222-1

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