Epigenetic Target Boosts Pancreatic Cancer Therapy

A new discovery in pancreatic cancer treatment has been made, indicating epigenetic silencing of BEND4 as a possible synthetic fatal signal for improving the efficacy of ATM inhibitors in pancreatic cancer treatment. This novel study offers a ground-breaking technique to targeting a tumor suppressor gene, BEND4, which is often methylated and silenced in pancreatic cancer. The study investigates the role of BEND4 in DNA damage repair and its potential as a therapeutic marker when paired with ATM inhibitor treatment.

The study followed a comprehensive technique that included cell line experiments, tissue sample analysis, and in vivo studies. The researchers examined the expression and methylation status of BEND4 in diverse pancreatic cancer cell lines and tissues and discovered a link between BEND4 methylation and poor tumour differentiation. Furthermore, BEND4 methylation has been discovered as an independent poor prognostic marker for individuals with pancreatic ductal adenocarcinoma (PDAC).

The study found that BEND4 reduces cell growth, promotes G1/S arrest and death, and prevents migration and invasion in PDAC cells. The underlying mechanism is BEND4’s interaction with Ku80, a crucial component of the non-homologous end joining (NHEJ) pathway, a significant DNA double-strand break (DSB) repair pathway. The study found that overexpressing BEND4 increased the efficiency of NHEJ, while knocking it down lowered it, indicating BEND4’s significance in DNA damage repair.

A key discovery of this study is the synthetic lethal effect of losing BEND4 expression in combination with ATM inhibitor treatment. The study found that PDAC cells with BEND4 methylation were more susceptible to the ATM inhibitor AZD0156, both in vitro and in vivo. This shows that BEND4 epigenetic silencing can be used as a biomarker to predict how pancreatic cancer patients will respond to ATM inhibitors.

The study also highlighted the possible clinical consequences of its findings. A novel treatment method could be created by targeting the ATM pathway in pancreatic cancer cells that have been silenced by BEND4. This method has the potential to lead to more successful treatments for PDAC patients, particularly those with BEND4 methylation, providing a promising path for improving outcomes in a disease with traditionally poor survival rates.

Finally, this study advances our understanding of the significance of epigenetically suppressed BEND4 in pancreatic cancer, as well as its potential to improve the efficacy of ATM inhibitor treatment. The findings give a solid basis for more study into the development of targeted treatments for PDAC, with a particular emphasis on leveraging the synthetic lethality of BEND4 methylation and ATM inhibitors. This study paves the path for more tailored and effective pancreatic cancer therapy options.

For more information: Yao, Y., et al. (2024) Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer. Frontiers of Medicine. doi.org/10.1007/s11684-023-1053-3.