Cancer cells are quick to develop resistance to anti-tumor drugs. New research by scientists from the University of California, Davis shows how cancers adapt to evade a class of anti-tumor drugs called BET inhibitors and offers hope for more effective therapies.
The researchers showed that when BET inhibitors eliminate their target protein, BRD4, cancer cells compensate by increasing the production of a related protein called BRD2, which takes over BRD4's epigenetic functions and allows the tumor to survive and grow. The team showed that many different cancers adapt to BET inhibition in this way, including pancreatic, blood, prostate, brain, breast, skin, and lung cancers. The results, published May 2 in Cellular and Molecular Biology Letters, suggest that developing a combination treatment that targets both proteins simultaneously could block resistance before it can take root.
"If cancer cells can compensate in this way, then just targeting BRD4 is not going to be sufficient," said first author Suyakarn (Sonia) Archasappawat, a Ph.D. candidate in the Graduate Group in Integrative Pathobiology. "Our results suggest that we could improve patient outcomes across multiple cancers by targeting BRD2 in combination with BRD4 inhibition."
Preventing cancer cell reprogramming
Cancer cells rely on epigenetic changes— alterations to the way that DNA is used—to grow, avoid the immune system, and spread. BET inhibitors are a class of potential cancer drugs that shut down this epigenetic reprogramming by targeting a BET protein called BRD4. In the lab, BET inhibitors are very effective at suppressing tumor growth, but they've been less effective in clinical trials.
"People have tried to develop BET inhibitor cancer treatments for a long time, but clinical responses have been modest and short-lived because cancers quickly develop resistance," said senior author Chang-il Hwang, an associate professor of microbiology and molecular genetics and a member of UC Davis Comprehensive Cancer Center. He is also Archasappawat's Ph.D. adviser. "Understanding how cancer cells adapt and respond to BET inhibition could reveal vulnerabilities and guide more effective therapies."
Following an unexpected clue
The project began when an unexpected datapoint caught Archasappawat's eye. In a separate study, the Hwang lab was investigating why a specific subtype of pancreatic cancer is particularly susceptible to BET inhibition. When Archasappawat examined the RNA sequencing data from those cancer cells, she noticed a marked increase in BRD2 expression after the cells were treated with a BET inhibitor.
"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.
Since there was almost no mention of this phenomenon in previously published papers, Archasappawat began digging through publicly available datasets to see if it had occurred elsewhere.
Altogether, she analyzed 51 datasets that examined how treatment with JQ1, the most well-studied BET inhibitor, affected gene expression. In all of the datasets—which included prostate, breast, brain, skin, gastrointestinal, lung, pediatric, gynecologic and blood cancers—JQ1 treatment was associated with increased BRD2 expression.
To confirm these results, the team treated eight different lab-grown mouse and human cancers with JQ1. In all cases, BRD2 transcription rates increased after JQ1 treatment. When they used genetic methods to reduce the cancers' ability to express BRD2, the cancers became more susceptible to treatment with JQ1 and other BET inhibitors.
"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, proliferate, and eventually metastasize."
Future research should focus on understanding the differences between BRD2 and BRD4 and developing drugs that specifically target BRD2, the researchers say. Targeting both BRD2 and BRD4 simultaneously could prevent resistance before it can start, which would improve treatment outcomes for patients.
"Most cancer patients have to undergo multiple rounds of treatment because of drug resistance — it's almost the expected next step — but I don't think it has to be inevitable," Archasappawat said. "If we can identify how cancer cells adapt to resist treatment, we may be able to intercept resistance before it fully locks in."
The study was coauthored by Juliette Jacques and EunJung Lee of UC Davis.
The work was supported by the National Cancer Institute (grant 5R37CA249007). Archasappawat was supported by the Anandamahidol Foundation (Thailand) and the UC Davis Comprehensive Cancer Center Director's Fellowship. Jacques was supported by the UC Davis Provost's Undergraduate Fellowship.
