Researchers at The University of Texas MD Anderson Cancer Center have identified an epigenetic target for replication stress, called DPY30, that could sensitise pancreatic tumors to immunotherapy and serve as a predictive biomarker for patients most likely to benefit from treatment.

The study, published in Cancer Research, was led by Francesca Citron, Pharm.D., Ph.D., instructor of Genomic Medicine, Andrea Viale, M.D., associate professor of Genomic Medicine , Katharina Schlacher, Ph.D., associate professor of Cancer Biology, and Giulio Draetta, M.D., Ph.D., former chief scientific officer.

“Understanding this new function of DPY30 as an epigenetic switch suppressing DNA replication stress in cancer cells can have a tremendous impact on future therapeutic strategies for pancreatic cancer patients, especially in combination with immunotherapy,” Citron said.

“We are encouraged by the potential to investigate this protein both as a predictive biomarker and as a therapeutic target to enhance immunotherapy response for patients with pancreatic cancer, who currently have limited effective treatment options.”

What is DPY30 and why investigate its role in cancer?

DPY30 is part of a group of proteins called the COMPASS complex, which helps control which genes are turned on or off by modifying how DNA is packaged inside cells.

In this study, the researchers discovered that DPY30 also directs the activity of this complex at DNA replication forks — critical sites where DNA is copied.

Replication forks are regions where the two strands of DNA separate to serve as templates for making new strands, a fundamental step in cell division.

The study shows that when DNA replication is disrupted, which is common in cancer cells, DPY30 helps protect these stressed replication forks, supporting cancer cell survival and continued growth.

What did the researchers find?

The researchers discovered that DPY30 promotes the addition of activation signals at stressed replication forks, helping to stabilise these structures and preserve genome stability.

In cancer cells, this function supports continued survival and proliferation despite ongoing replication stress and DNA damage.

Conversely, loss or depletion of DPY30 destabilises replication forks, leading to increased genomic instability and the activation of inflammatory signalling pathways.

This, in turn, promotes immune cell infiltration into tumors and supports the development of long-term antitumor immunity, effectively converting previously immunologically “cold” tumors into more responsive, “hot” tumors that are sensitised to immune checkpoint blockade.

Overall, these findings reveal that DPY30 has a replication stress-specific role that is distinct from its known function in transcriptional regulation and highlights its potential as both a predictive biomarker and a therapeutic target in cancer.

What does this mean for potential treatments?

Patient samples of pancreatic cancer with higher levels of DPY30 tend to have higher tumour grades, a poorer prognosis and an inferior response to immunotherapy.

Therefore, DPY30 could serve as a potential predictive biomarker to stratify patients most likely to benefit from treatment.

Additionally, these results suggest that targeting DPY30 in pancreatic cancer cells could help sensitise tumours to immunotherapy, improving patient outcomes.

Further evaluation is needed before this can be applied to clinical trials.

Source: The University of Texas MD Anderson Cancer Center