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New Insights into the Pathogenesis and Treatment of the Most Aggressive Form of Pancreatic Cancer

Loss of KDM6A, an X chromosome-encoded tumor suppressor, was found to induce squamous-like and metastatic pancreatic cancer

Alexandros TzatsosResearch published in Cancer Cell by George Washington University (GW) Cancer Center researcher Alexandros Tzatsos, MD, PhD, found an important connection between the KDM6A gene and the most aggressive form of pancreatic cancer.

The study found that the loss of KDM6A, an X chromosome-encoded histone demethylase, induces a histologically distinct subtype of pancreatic cancer, known as “squamous-like.” Tzatsos and his team also identified that KDM6A is frequently mutated or deleted in this type of pancreatic cancer and functions as a tumor suppressor. They found that bromodomain and extra-terminal (BET) inhibitors, a class of small molecules that are currently in clinical trials for treating several malignancies, may be a promising therapy in treating the disease by restoring cell identity and sensitizing tumors to current therapies.

“Squamous-like pancreatic cancer is an aggressive and highly metastatic subtype of the cancer,” explained Tzatsos, who is also an assistant professor of anatomy and regenerative biology at the GW School of Medicine and Health Sciences. “By using the KDM6A knockout cell lines, we found that squamous-like pancreatic cancer is sensitive to BET inhibitors.”

According to the American Cancer Society, pancreatic cancer accounts for about three percent of cancers in the United States, but about seven percent of all cancer deaths. Four subtypes of pancreatic cancer have been identified in recent years: squamous-like, aberrantly differentiated endocrine exocrine, pancreatic progenitor, and immunogenic. The squamous-like subtype offers the worst prognosis and accounts for 20-30 percent of pancreatic cancer cases.

“Following our research,” said Tzatsos, “the next step is to develop targeted therapies for this type of pancreatic cancer by combining BET and other small molecule inhibitors.”

The study, titled “Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors” is available in Cancer Cell at