Genetic errors can drive cancer, often when critical genes like those that control cell division and proliferation become impaired. Cancer cells can also acquire mutations in genes that are necessary for cell survival, causing the cell to rely on other genes to live. It may be possible to use those genes as therapeutic targets in the fight against cancer, so these cells no longer have a way to get by.
Scientists have now identified two related genes that cancer cells often end up depending on; they found that when one of the two genes VPS4A or VPS4B becomes deactivated, tumor cells start to use the other gene to compensate for the loss. This so-called genetic dependency might be present in as many as one-third of all cancers, noted the researchers. If a drug was aimed at the gene that a tumor had become dependent on, either VPS4A or VPS4B, it could potentially kill those tumor cells.
In this study, which was published in Cell Reports, the researchers utilized either CRISPR or RNA interference to screen 873 cell lines from over two dozen types of cancer in which genes that are known as tumor suppressors had been deactivated or deleted. These tumor-suppressor genes regulate cell growth and keep it under control; when they stop working, cell growth happens unchecked, and a tumor forms.
"Tumor suppressors are hard to target therapeutically," said co-first study author Brenton Paolella, a research scientist with the Cancer Dependency Map (DepMap) team and the Broad Institute's Cancer Program. "But we realized we had an opportunity to find new targets by looking for other genes associated with tumor suppressor loss."
Cells lines that lost one of two genes, CDH1 or SMAD4, which are known tumor suppressors commonly deleted in cancer, showed that VPS4A and VPS4B were candidates. VPS4A is in close proximity with CDH1 on chromosome 16, so it often ends up deleted too. VPS4B and SMAD4 are similarly connected on chromosome 18.
Many different kinds of cancer, including bladder, breast, gastric, liver, pancreatic, lung, ovarian, and colorectal cancers were found to depend on either VSP4A or VPS4B. In the Cancer Genome Atlas, 33 percent of all cancers were found to have lost VPS4B while 27 percent had lost VPS4A.
When the researchers deleted the VPS4A genes from cancer cells that lacked VPS4B, they found that the cells were vulnerable.
"This is another great example of the power the cancer dependency map holds for identifying targets that would be difficult to pinpoint by just profiling a tumor's molecular information," said DepMap associate director and institute scientist Francisca Vazquez.
Sources: Broad Institute, Cell Reports
