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Scientists from the Cancer Dependency Map (DepMap) at the Broad Institute of MIT and Harvard, alongside Columbia University, have made a groundbreaking discovery that could revolutionize cancer treatment. Their research, published in Nature, reveals that approximately 5% of adult cancers depend heavily on a gene called PELO for survival, and that disabling this gene can effectively kill cancer cells. This discovery opens the door for targeted therapies for cancers with mutations in two specific genes: FOCAD and TCC37.
The researchers focused on a new phenomenon known as synthetic lethality, where two genetic changes in cancer cells together result in the death of the cell. In this case, cancer cells with mutations in either FOCAD or TCC37 are vulnerable to a loss of PELO. This finding suggests that drugs targeting PELO could prove beneficial for patients with these mutations, offering a much-needed therapeutic option for cancers that currently lack effective treatments.
“These cancers are a huge unmet medical need, because we don’t have effective drugs for them,” said Francisca Vazquez, co-senior author of the study and director of DepMap. She highlighted the potential of PELO as a promising drug target, noting that genetic testing could identify patients who might benefit from such therapies.
The study began by examining cancers with deletions on chromosome 9, specifically in the 9p21.3 region, which is common in aggressive cancers such as those of the brain, bladder, pancreas, esophagus, and lungs. The team discovered that cell lines with deletions in this region were particularly reliant on PELO. Further investigation revealed that mutations in FOCAD and TCC37 triggered this dependency, which could have implications for colorectal and endometrial tumors as well.
PELO encodes a protein involved in restarting ribosomes when they stall due to defective mRNA during protein production. The research showed that mutations in FOCAD and TCC37 led to lower levels of their proteins, causing the cells to depend on PELO to resume protein production. When PELO is disabled, the cells are unable to restart the process and ultimately die.
While the discovery has great potential for improving cancer treatment, the team aims to conduct further research to better understand the role of PELO and the superkiller complex in human cells. They also plan to explore the development of a drug that could inhibit PELO effectively, potentially broadening the scope of cancers that could benefit from this treatment.
Francisca Vazquez is optimistic that additional synthetic lethal relationships involving PELO may exist, expanding the pool of patients who could benefit from PELO-targeting drugs in the future.
Disclaimer: This research is in its early stages and further studies are required before new treatments can be developed and made widely available. The information shared in this article reflects the current findings and the potential for future therapeutic strategies, but it should not be interpreted as conclusive medical advice.
For more information, refer to the original study: Patricia C. Borck et al, SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO, Nature (2025). DOI: 10.1038/s41586-024-08509-3.
