Nature sub-journal: Gene 'Achilles heel' found in ovarian and uterine cancers

Introduction: Recent research has identified a genetic "Achilles heel" in ovarian and uterine cancers
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The XPR1 gene is a genetic vulnerability in these cancer cells, and phosphate accumulation may be toxic to the cells
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Disrupting phosphate transport in cancer cells, such as with a protein experimentally used to disable XPR1, could be an effective therapeutic strategy
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Although the outlook for certain types of cancer has improved over the past 20 years, outcomes for patients with uterine and ovarian cancers remain about the same
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Patients often have advanced disease before they are diagnosed, and the genes that drive tumor formation have proven difficult to target with new treatments
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Now, researchers from the Dependency Map of Cancer (DepMap) project at the Broad Institute of MIT and Harvard have identified a hidden vulnerability in ovarian and uterine cancer -- and a way to exploit it that could inspire these New, much-needed drugs for cancer
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A team led by Institute Director Todd Golub and DepMap Director Francisca Vazquez studied 851 human cancer cell lines, looking for genes that uterine and ovarian cancers rely heavily on for survival
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Scientists already knew that uterine and ovarian cancer cells contain a protein called SLC34A2 that imports phosphate into cells
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Golub's team disabled another protein, called XPR1, in these cells, which exports phosphates from the cells, and found that this killed them
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The findings, "Phosphate dysregulation via the XPR1–KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer," published in Nature Cancer, suggest that the XPR1 gene is a genetic vulnerability in these cells, and that phosphate accumulation may affect the cells.
Toxic
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Disrupting phosphate transport in cancer cells, such as with a protein they used to disable XPR1 in their experiments, could be an effective therapeutic strategy, the team added
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"Ovarian cancer patients desperately need better therapies, and this XPR1 discovery as a starting point for drug discovery is both surprising and exciting," said Golub, who co-led the project
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"The challenge now will be to translate this discovery into a therapeutic strategy
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"This is another great example of a new cancer vulnerability discovered by Depmap that cannot be identified by sequencing the genome alone," said Francisca Vazquez, co-senior author of the study
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DepMap allows them to elucidate biological pathways and open up new questions in an unbiased manner
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Phosphate flooding

Phosphates — a single phosphorus atom surrounded by four oxygen atoms — are essential to life, found in minerals in bones and teeth and in the backbone of DNA
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Although previous studies have shown abnormally high levels of the phosphate import protein SLC34A2 in ovarian cancer cells, the protein is present in other tissues such as the lungs and gut, so targeting it with drugs could cause side effects
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To find better targets for future therapeutics, the team focused on finding vulnerabilities unique to uterine and ovarian cancer cells
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They combed through DepMap's CRISPR screens, showing the effect of disabling key genes in cancer cells
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In 851 cell lines, they observed that when XPR1, which encodes the only protein known to export phosphates from cells, was turned off, uterine and ovarian cancer cells were more likely to die than other cells
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In particular, XPR1-inactivated cells died only when a large amount of phosphate was infused at the same time
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Also, in these cells, another molecular feature most frequently found is high levels of importins
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Next, Golub's team found evidence of a correlation between phosphate input and output in archived patient data
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Bondeson and Paolella say the relationship presents a clear hypothesis: The buildup of phosphate is itself toxic
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for treatment

Back in the lab, the team tested their theory
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In ovarian and uterine cell models, they found that when the cells highly expressed the imported genes, the cells depended on XPR1 for survival
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And when they inactivated XPR1 or inhibited it with a protein, the cells accumulated phosphate, grew more slowly, and eventually died
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The scientists say that the protein they used to inhibit XPR1, with further development, could be a potential treatment for these cancers, and Golub's lab will continue to investigate whether such proteins are a viable therapeutic strategy
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"Some of the genetic dependencies of ovarian cancer are difficult to target with drugs, but we showed that we can actually target XPR1 with a protein that kills cancer cells," Bondeson said.
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That's really exciting
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The team also observed that XPR1 dependence was closely related to dependence on another gene called KIDINS220, which is involved in neural development but has not been previously linked to phosphate transport
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The researchers think that XPR1 and KIDINS220 come together to form a protein complex involved in transporting phosphate out of the cell
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This link raises a host of other scientific questions: Could KIDINS220 also be a target for new drugs? Do diseases associated with KIDINS220 involve phosphate regulation?

Bondeson and Paolella say the involvement of KIDINS220 in phosphate transport shows that there is still a lot to learn about how XPR1 and KIDINS220 interact with each other and with phosphate -- and more fundamentally, in the scientific understanding of how cells sense, regulate and There are still deep gaps in the storage of phosphates
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Exactly how the buildup of phosphate kills cells remains to be figured out, they add
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For example, they noticed unusual membrane-encapsulated sacs in microscope images of phosphate-laden cells
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They didn't know whether the sacs or vacuoles were storing extra phosphate or signs of imminent death
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References:

https://medicalxpress.
com/news/2022-04-genetic-achilles-heel-ovarian-uterine.
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