Researchers reveal how entinostat disrupts pancreatic cancer repair

Pancreatic cancer is one of the deadliest forms of the disease and ranks as the third leading cause of cancer-related death in the United States. While efforts to develop new therapies continue, scientists say understanding how existing drugs work can also help to inform important new treatment opportunities.

Now, researchers at the Salk Institute have discovered how an existing investigational cancer drug works in pancreatic cancer. The findings focus on entinostat, a drug that inhibits enzymes known as histone deacetylases (HDACs). 

Understanding HDAC inhibitors

Scientists have long been interested in HDAC inhibitors because of their anti-cancer potential. However, the drugs have produced mixed results in clinical settings, partly because they can also affect healthy cells.

“HDAC inhibitors have shown promise as cancer therapies but they have not worked as well as researchers had hoped, in part due to toxicity issues,” says co-corresponding author of the study Dr Ronald Evans, Professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. “Scientists have not fully understood how these drugs work in different cancers or how to use them more effectively. We set out to change that.”

HDAC inhibitors have shown promise as cancer therapies, but they have not worked as well as researchers had hoped, in part due to toxicity issues

Researchers examined human and mouse pancreatic cancer cells to investigate how gene activity changed after treatment with entinostat. They discovered that HDACs play a previously unrecognised role in helping cancer cells repair damaged DNA.

According to the team, HDACs help keep DNA repair genes active, allowing tumours to recover from damage and continue growing. When HDAC activity was blocked with entinostat, these repair genes became less active, leaving cancer cells more vulnerable.

Making treatments more effective

Many existing pancreatic cancer treatments, including chemotherapy and radiotherapy, work by causing DNA damage. However, cancer cells often evade destruction by rapidly repairing that damage.

“The activity of DNA damage repair genes is one reason why chemotherapy and other DNA-damaging therapies often have limited effectiveness,” says first author Gaoyang Liang, a staff scientist in Evans’s lab. “By combining entinostat with DNA-damaging therapies, we were able to make these treatments significantly more effective in pancreatic cancer models.”

The activity of DNA damage repair genes is one reason why chemotherapy and other DNA-damaging therapies often have limited effectiveness

The study also revealed why HDACs have this effect. Rather than simply controlling whether genes are switched on or off, the enzymes help direct the cell’s transcriptional machinery towards important functions, including DNA repair.

“Think of HDACs as operations managers that help direct the cancer cells’ resources towards critical functions like DNA repair,” says Liang. “When we blocked HDAC activity, the cells lost that direction and could not keep DNA repair genes active anymore, making them vulnerable to DNA damage.”

Reducing side effects

The team also explored ways to improve the drug’s tolerability, as toxic side effects have been a major obstacle to the wider use of HDAC inhibitors.

“People looked at HDAC inhibitors like entinostat – it has meaningful anti-tumour effects but it can also cause toxicities,” says co-author Dr Morgan Truitt, a staff scientist in Evans’s lab. “When you have a drug like that, it makes you wonder how you can make it work better clinically.”

Working with collaborators at MIT, researchers developed a nanoparticle-based version of entinostat using bottlebrush-shaped particles designed to accumulate in tumours and release the drug gradually. In preclinical models, the approach maintained strong anti-tumour activity while reducing toxicity.

Now the researchers believe the findings could have implications beyond pancreatic cancer, as many tumours rely on DNA repair mechanisms to survive treatment. Further work will focus on refining the nanoparticle system and exploring ways to deliver entinostat alongside DNA-damaging therapies, potentially creating more effective cancer treatments in the future.