Why BET Inhibitors Fail in Estrogen-Driven Breast Cancer and How to Improve Them
Key Insights
A new study explains why BET inhibitors (search), promising for other cancers, are ineffective against estrogen receptor-positive breast cancer (search), revealing they only partially block oncogene activation.
Researchers found that cancer-related genes depend on the BET protein itself, not just its bromodomain, and BRD4 can activate MYC (search) without relying on its bromodomain.
The study identified that BRD4 interacts with the Mediator complex, crucial for gene transcription and estrogen receptor function, independent of the bromodomain.
Hopes were high a decade ago when BET inhibitors (search) emerged as a new class of drugs for treating blood cancers and solid tumors. However, clinical trials have revealed a more complex picture, especially in breast cancer (search). A new study published in Nature Structural & Molecular Biology explains why this therapy, which shows promise in other cancers, is ineffective against a common form of breast cancer.
The Problem with BET Inhibitors in Breast Cancer
"We figured out that these therapies block only one part of the protein that activates the oncogenes," says Robert G. Roeder, the Arnold and Mabel Beckman professor. "It turns out that isn’t enough."
Cancer researchers have long targeted the BET protein family, particularly BRD4, due to their activity in many cancer-related genes and pathways. These proteins use the bromodomain to bind to acetylated histones, acting on genes that promote cell survival. In breast cancer (search), BET proteins trigger a runaway transcription cycle, leading to uncontrolled cancer cell proliferation. The initial hope was that BET inhibitors (search), designed to block the bromodomain, would halt this cycle.
However, clinical trials have repeatedly failed to demonstrate the efficacy of BET inhibitors (search), especially in estrogen receptor-positive breast cancers. "We had already been looking into how this estrogen receptor positive breast cancer (search) is driven by transcription when the first clinical trials of these BET inhibitors failed," says Sicong Zhang, first author on the paper. "There was no explanation for why they should have failed. We wanted to figure out what went wrong."
Unveiling the Mechanism of Resistance
Zhang and Roeder used advanced techniques to investigate BET proteins’ role in gene transcription. They compared the effects of blocking BET proteins with inhibitors versus completely removing them. The results showed that cancer-related genes like MYC (search) depend on the BET protein itself, rather than just its bromodomain. The team also engineered bromodomain-less BET proteins to study their behavior. Among the different BET proteins, only BRD4 was able to activate MYC without relying on its bromodomain. When BRD4 was removed from cells, BET inhibitors (search) completely killed cancer cells.
The Role of the Mediator Complex
Further investigation revealed that BRD4 interacts with a protein complex called Mediator, which plays a major role in gene transcription and works directly with estrogen receptors. Disrupting Mediator’s function significantly decreased BRD4’s ability to bind to certain regions of genes. This interaction between BRD4 and Mediator does not depend on the bromodomain, suggesting that BRD4 is recruited to genes in another way.
Using a new method called MSDC (mass spectrometry with DTME crosslinking), the researchers found that BET proteins help RNA polymerase II (search) find its associated elongation factors (SPT5, SPT6, PAF1 complex). These elongation factors work closely with RNA polymerase II to keep transcription running smoothly, and BET proteins can interact with these elongation factors independently of the bromodomain.
In essence, BET inhibitors (search) effectively block BRD4’s bromodomains, but this is insufficient to fully block the protein’s oncogenic activity.
Future Directions
The findings underscore the need for a more thorough understanding of BRD4. Zhang and Roeder are now focusing on this goal. "We still don’t have a high-resolution atomic structure of the BRD4-Mediator complex," Roeder says. "That’s now on the agenda." They are also considering whether a combination therapy that targets both BRD4’s bromodomain and its various transcriptional backdoors might lead to a more effective BET inhibitor.
"We know why BET inhibitors (search) failed," Zhang says. "Now we’re trying to make one that works."