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Scientists are on the right TRAIL to tackle a special type of treatment resistance

Researchers funded by Worldwide Cancer Research have uncovered how cancer cells become resistant to a type of targeted treatment that aims to trigger a biological mechanism that causes cells to die. The researchers hope that their work could lead to the development of new therapies that can help combat resistance.

The study, led by scientists at the University of Strasbourg, France, looked at how cancer cells respond to a biological molecule, called TRAIL, and the role it plays in determining if a cancer cell lives or dies. TRAIL belongs to a class of signalling molecules called cytokines that bind to receptors in the cell membrane and kick start a cascade of signals that forces the cell to die. TRAIL is an important molecule that is used by specialised cells of our immune system to destroy cancer cells when they arise in the body.

Unlocking the secret of TRAIL

An exciting discovery made by scientists - that TRAIL kills cancer cells without affecting normal ones - kicked off a new area of cancer therapy that aims to take advantage of this by using drugs that activate the TRAIL signalling cascade to kill cancer cells. These therapies showed promise when tested in the lab, but it was noted that cancer cells often became resistant to the treatment over time, and in clinical trials, only very few patients benefitted from the various types of treatments tested. How this happened was unclear but, if we can work it out, it could be possible to improve TRAIL pathway-based therapies.

The team in France, led by Dr Hinrich Gronemeyer, found that cancer cells react to TRAIL therapy in opposing ways. Sometimes they are pushed towards cell death and sometimes they are primed to survive. This duality creates two problems; first, cancer cells were never completely eradicated even if they responded in such a way that most of them were killed, and second, the surviving cancer cells allowed the cancer to persist and develop resistance to treatment in the long term.

Dr Gronemeyer explained: “Our study reveals the “Janus” face of TRAIL signalling in cancer cells – specifically, we found that a single TRAIL receptor can promote both cell death and cell survival in cancer cells. Our data suggest that the environment in which this receptor is positioned in the cell membrane is critical for signalling that promotes cell death or cell survival. This has important ramifications for TRAIL-based therapies because their improper use may actually stimulate tumour growth. The future goal must be to design combination therapies, which carries the exciting possibility to selectively kill cancer cells by TRAIL while simultaneously blocking survival signals in cancer cells.”

Beating resistance is a top priority

It’s well known that cancer cells develop resistance to treatments, so understanding how to prevent resistance is crucial for the development of more successful treatments. Most of the time resistance is driven by the fact that all cancer cells within a tumour are not genetically identical. Cancer cells with genetics that make them resistant are left behind following treatment and continue to grow. In contrast, Dr Gronemeyer’s findings show that, in this case, resistance isn’t driven by genetics, but is an inherent component of a natural biological mechanism, which scientists refer to as “fractional killing”. Simply put, some cells are driven to death and some to survive by the same mechanism, leaving behind a fraction of cancer cells that are resistant to further treatment.

Finding novel ways to stop cancer cells becoming resistant to treatment is a key priority if we are to stop people dying from the disease. The clever experiments carried out by Dr Gronemeyer and his team show why basic research is so important for understanding the biological mechanisms of cancer and the development of new treatments.

The original research article is available to read for free here: https://www.nature.com/cddis/journal/v8/n8/full/cddis2017423a.html

Science Communications Manager

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