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New discovery may lead to treatments for small-cell lung cancer

An estimated 13% of diagnosed lung cancer is SCLC. According to the National Organization for Rare Diseases, SCLC is an aggressive type of cancer “characterized by rapid, uncontrolled growth of certain cells in the lungs.”

If SCLC is caught early and before it has spread, treatments can control the disease in up to 25% of cases.

The authors of the recent study wanted to understand the role of EP300 gene mutations in SCLC.

Medical News Today spoke with the corresponding authors of the study:

  • Dr. Kwon-Sik Park — associate professor of microbiology, immunology, and cancer biology at the University of Virginia School of Medicine in Charlottesville.
  • Dr. John Bushweller — professor of molecular physiology and biological physics at the University of Virginia.

“The current prognosis for SCLC patients is particularly poor with only 7% of patients surviving beyond 5 years. This reflects a lack of well-validated targets for therapy and a concomitant lack of targeted agents to treat the disease,” they explained.

“It is critical to garner further insights as to the drivers of the disease as well as develop drugs targeting those drivers. However, relevant pre-clinical models of SCLC carrying recurrent driver mutations were scarce, precluding the study to assess the physiological role of the mutations and the therapeutic impact of restoring their normal functions. So we built pre-clinical models using genetically engineered mice and cells.”

Target for drug development

By studying genetically engineered mouse models, the researchers found that EP300 — the protein that the EP300 gene codes for — can either promote or inhibit SCLC.

Specifically, they found that part of the EP300 protein — known as the KIX domain — was essential for the development of SCLC.

“EP300 is a multi-functional protein and loss of its histone acetyltransferase domain function — as predicted based on the mutations observed in SCLC patient tumors — drives the cancer. This idea was validated by the findings from the pre-clinical models,” they explained.

“Unexpectedly, however, the models also showed that the KIX domain of the mutant EP300, which remains intact, drives the disease. Specifically, the protein-protein interactions mediated by the KIX domain of EP300 are critical for the survival of SCLC cells and vulnerable to inhibition. This was shown both in a mouse model as well as using human SCLC cell lines.”

“This validates the KIX domain of EP300 as a target for drug development for the treatment of SCLC, specifically a protein-protein interaction inhibitor of the KIX domain,” said Drs. Park and Bushweller.

The finding may also have relevance for other types of cancer. According to the corresponding authors, “EP300 mutations are widespread and have been implicated as having a critical role in other cancers including leukemia and triple-negative breast cancer.”

MNT spoke with Dr. Charles Evans, research information manager at Cancer Research UK, who was not involved in the study.

“Right now, we only have a limited range of chemotherapy treatments available for people with small-cell lung cancer — many of which can have harsh side effects,” said Dr. Evans.

“This study highlights a potential vulnerability for small-cell lung cancers, which could be exploited with new, targeted drugs in the future. However, more studies will be needed to confirm these results and develop a new treatment approach.”

New treatments

Dr. Evans said that the findings were one of a number of potential new treatment options for cancer.

“There are other promising areas of research that are happening right now, such as the development of immunotherapies that can harness the power and precision of our immune systems to tackle cancer.”

“And innovations in radiotherapy, including new techniques such as proton beam therapy, have the potential to target tumors with a stronger dose far more precisely, limiting damage to surrounding tissue and reducing the burden of long-term side effects from treatment.”

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