Gene Fusion Causes Cancer by Boosting Mitochondria Activity

Mitochondrial inhibitors may be a beneficial add-on therapy for glioblastoma containing gene fusion.

Gene fusion has been implicated in multiple types of cancer. Recent research finds that targeting this process may present patients with a more effective therapy.

A recent study published by Nature found that gene fusion causes mitochondria to go into overdrive and drastically increases fuel available for cell proliferation.

Importantly, the researchers discovered a pathway that prohibits tumor growth in both cell and mice models of brain cancer.

A previous study showed that certain cases of glioblastoma were caused by the fusion of the FGFR3 and TACC3 genes. While this finding was originally limited to a limited number of brain cancers, other research has shown that the gene fusion also results in lung, esophageal, breast, head and neck, cervical, and bladder cancers, according to the authors of the current study.

“It’s probably the single most common gene fusion in human cancer,” said study co-leader Antonio Iavarone, MD. “We wanted to determine how FGFR3-TACC3 fusion induces and maintains cancer so that we could identify novel targets for drug therapy.”

Although changes in mitochondria have been known to play a role in cancer, the relationship between mitochondrial activity and cellular metabolism have only been recently linked to cancer, according to the authors. However, the way in which genetic mutations amplify mitochondrial activity and increase tumor growth was not understood.

In the current study, the authors analyzed the mitochondrial activity of thousands of genes in cancer cells both with and without FGR3-TACC3.

The results suggest that gene fusion sparks an uptick in the number of mitochondria and speeds up its activity, according to the study. These actions help cancer cells proliferate because they require a significant amount of energy to survive.

The authors discovered that FGFR3-TACC3 sparks a cascade of events that results in increased mitochondrial activity.

First, the fusion gene activates the PIN4 protein. The protein then travels to peroxisomes, which are cellular structures that break down fats to fuel mitochondrial activity, according to the study.

The authors also found that activated PIN4 results in a 4- to 5-fold increase in peroxisome production, resulting in a release of oxidants that induce PGC1 alpha, a regulator of mitochondrial metabolism.

“Our study offers the first clues as to how cancer genes activate mitochondrial metabolism, a crucial and longstanding question in cancer research, and provides the first direct evidence that peroxisomes are involved in cancer,” said study co-leader Anna Lasorella, MD. “This gives us new insights into how we may be able to disrupt cancer’s fuel supply.”

After the mechanisms of gene fusion were discovered, the authors conducted an experiment in human brain cells. They found that treating cells containing FGR3-TACC3 with mitochondrial inhibitors blocked energy production and reduced tumor growth, according to the study.

A similar result was seen in mouse models of brain cancer with the gene fusion.

The authors hypothesize that a dual treatment approach with current drugs and a mitochondrial inhibitor may be necessary for patients with tumors containing FGR3-TACC3.

Previously, the researchers found that FGFR3 kinase inhibitors increased survival of mice with glioblastoma. This therapy is now being tested in patients with glioblastoma containing FGR3-TACC3, according to the study.

“Drugs that inhibit active kinases have been tried with encouraging results in some cancers,” Dr Iavarone said. “But invariably, they become resistant to the drugs, and the tumors come back. However, it may be possible to prevent resistance and tumor recurrence by targeting both mitochondrial metabolism and FGFR3-TACC3 directly.”