FDA-approved cancer drug fedratinib reshapes how cell organelles communicate, providing new therapeutic avenues

Cells behave like cities and organelles carry out infrastructural roles: mitochondria are powerhouses, the endoplasmic reticulum serves as a transport hub and lysosomes help with waste disposal. Communication between different parts of a cell is important for metabolism. This inter-organelle communication can occur at sites where these parts are in contact with each other, known as membrane contact sites.

One of the most abundant interactions occurs at the endoplasmic reticulum and mitochondria contact sites, or ERMCS, and dysregulation leads to various diseases, including neurodegeneration, obesity, cancer and diabetes. However, little is known about what drives ERMCS organization.

In a new study, University of Michigan researchers found that the FDA-approved drug fedratinib can lead to ERMCS formation, providing a potential therapeutic avenue. The paper is published in the journal Molecular Cell.

Using human and mouse cell lines, the researchers screened a library of FDA-approved drugs to see which ones can influence ERMCS formation. They found that the anti-cancer drug fedratinib could do so, and this increase was reversible when fedratinib was washed away from the cells.

The team found that fedratinib inhibits BRD4, a protein that controls how DNA is read by the cells in a process called transcription. This inhibition activates a transcriptional pathway that induces ERMCS formation.

“Over the past few decades, researchers have seen that cell organelles work in conjunction and they need to talk to each other to do that,” said Yatrik Shah, Professor of Molecular and Integrative Physiology and member of the Rogel Cancer Center. “By identifying this signaling pathway, we can better understand how these contact sites are sustained.”

Using electron microscopy, the researchers showed that fedratinib also caused novel structural changes in the ERMCS sites. These changes were similar to what is seen when cells are infected with SARS-CoV-2 and in metastatic melanoma cells.

“We found 3D envelopment of the endoplasmic reticulum that formed around the mitochondria in our cell lines,” said Drew Stark, a graduate student in the Shah and Lyssiotis labs and the first author of the paper.

“There were also different populations of mitochondria that differed in their degree of contact with the endoplasmic reticulum.”

Approximately 30% of the mitochondria exhibited structural alterations, and the researchers believe that those with abundant contact sites are being used to support specific metabolic pathways.

The researchers are investigating whether the same effects are seen in mouse models. They also aim to understand how these mitochondria are affecting metabolic processes and whether they have similar roles in other diseases.