When Suyakarn Archasappawat first noticed the odd data point, she almost overlooked it. The graduate student was studying a type of pancreatic cancer that seemed to respond well to a certain drug. But when she looked closer at the gene activity in those cancer cells, something strange had happened: the cells had cranked up production of a different protein entirely. "I was so puzzled, but I thought it might be something that the cells do to adapt and survive under pressure of the treatment," she said. That single observation, made in a lab at the University of California, Davis, has now led to a discovery that could help cancer patients everywhere.
Archasappawat and her team have figured out how cancers fight back against a promising class of drugs called BET inhibitors. These drugs work by shutting down a protein called BRD4, which cancers need to grow and spread. In laboratory experiments, BET inhibitors work beautifully. But in actual patients, tumors often find a way to survive anyway.
The answer, the researchers found, lies in a close relative of BRD4 called BRD2. When BET inhibitors block BRD4, cancer cells simply produce more BRD2, which takes over the same jobs and keeps the tumor alive. To confirm this was a widespread trick, Archasappawat dug through 51 different studies testing a BET inhibitor called JQ1. In every single dataset, from prostate and breast cancers to brain tumors and blood cancers, the same pattern appeared: BRD2 levels jumped when BRD4 was blocked.
The team then tested the idea backwards. They used genetic methods to reduce cancer cells' ability to produce BRD2, then treated the cells with BET inhibitors. The cancers became far more vulnerable to the drugs. "This shows that BRD2 upregulation contributes to cancer resistance against BET inhibitors," Archasappawat said. "If you close a major highway, the traffic doesn't disappear, it just reroutes. BRD2 is the alternative route that cancer cells use when BRD4 is shut down so that they can survive."
The findings, published in May in the journal Cellular and Molecular Biology Letters, point toward a new treatment strategy. Rather than targeting just BRD4, doctors could potentially use a combination therapy that hits both BRD2 and BRD4 at the same time, closing both highways before the cancer can find a detour.
"If cancer cells can compensate in this way, then just targeting BRD4 is not going to be sufficient," Archasappawat said. "Our results suggest that we could improve patient outcomes across multiple cancers by targeting BRD2 in combination with BRD4 inhibition."
Her advisor, Chang-il Hwang, an associate professor of microbiology and molecular genetics at UC Davis, said that understanding exactly how cancers adapt could reveal weaknesses that doctors can exploit. The discovery offers new hope that drugs currently being tested in clinical trials might finally work better for patients with pancreatic, lung, breast, brain, and other cancers.