Metastatic uveal melanoma is a rare and aggressive cancer with limited treatment options. Unlike the more common cutaneous melanoma, which responds well to immunotherapies such as immune checkpoint inhibitors, uveal melanoma remains largely resistant to such treatments.
As of now, the only effective medication that is accepted is tebentafusp, which only works in a small group of people with the HLA-A*02:01 allele. However, despite significant advances in understanding the biology of this disease, no highly effective targeted treatments have been developed. Consequently, the survival rates of people living with metastatic uveal melanoma are very low.
Researchers have discovered a new genetic vulnerability, providing hope for patients with uveal melanoma, a rare and aggressive form of eye cancer. CDS1 and CDS2 are homologous genes that participate in phosphoinositide synthesis and were detected within the study. Specifically, cancer cells that expressed low levels of CDS1 became dependent on CDS2 for survival. This dependency indicates a synthetic lethality. When CDS2 is disrupted in cells that are low in CDS1, they are unable to survive, as shown in both cell line and in vivo mouse models. The finding was reported in Nature Genetics and could lead to new treatment not only of uveal melanoma, but also of other various types of cancer as well.
They used a sophisticated CRISPR-Cas 9 screen in ten well-characterized uveal melanoma cell lines to identify novel therapies. The researchers conducted a genome-wide screening that comprised single-gene as well as paired-gene knockouts. This was aimed at discovering some of the crucial genes that can be used by the cancer cells to survive in situations where the existing therapies fail or when they are limited in number.
Researchers examined 514 pairs of genes, some paralogs (genes that have similar functions and evolution), and investigated how cells responded to the disruption of one or both genes. They have also analyzed data related to Pan-cancer collected in such large genetic databases as TCGA and DepMap to define whether their results would be applicable to other cancer types.
Out of the gene pairs tested, a total of 105 were determined to be “synthetic lethal” in at least one cell line. Of these, the combination of CDS1 and CDS2 proved to be the most promising. In cancer cells expressing low CDS1 levels, the disruption of CDS2 resulted in a significant decrease in cell survival, which resulted in apoptosis (programmed cell death).
Most importantly, the team confirmed that this relationship between CDS1/CDS2 is applicable in many other cancers beyond uveal melanoma. They observed that other cancers, such as glioblastoma, sarcoma, breast cancer, and cutaneous melanoma, often have low CDS1 expression, and it looks like targeting CDS2 in those cases could work too.
Mechanistically, CDS2 loss led to problems in the synthesis of essential cellular lipids, leading to accumulation of toxic intracellular lipid droplets and depletion of important signaling lipids like phosphoinositides, all of which induce stress and death in cancer cells.
Additional experiments involving live mice further revealed that tumor growth decline in uveal melanoma models occurred when CDS2 was inhibited. Remarkably, this effect continued even over a month, with no signs of resistance, highlighting its promising therapeutic potential.
The research here identifies CDS2 as the central point of vulnerability in low-expressing cancers of CDS1. Since CDS1 and CDS2 are involved in a similar mechanism of tumor growth through lipid signaling pathways, this synthetic lethal effect will be an innovative and promising tool for drug development.
Researchers believed it may be feasible to develop therapeutic interventions to prevent CDS2, especially in cases of low CDS1 expression in malignancies. These findings represent a significant advancement in precision medicine, proposing more responsive and targeted treatments for uveal melanoma and other treatment-resistant cancers. Further research is needed to formulate safe drugs that preferentially target CDS2, while sparing healthy tissues.
References: 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. doi:10.1038/s41588-025-02222-1
