Cancer cells learn how not to die

Cancer cells can learn how not to die. They can evade programmed cell death, a natural "self-destruction program" that normally gets rid of damaged cells. This can make them resistant to therapy. A current review article in the renowned journal Cell shows how these survival mechanisms might specifically become the Achilles heel of tumor cells. Medical University of Graz researchers Philipp Jost and Adam Wahida are both involved in the international collaboration.

When cell death becomes therapy

A healthy body selectively gets rid of cells that are damaged or no longer necessary. Apoptosis, or programmed cell death, plays a key role in this process. "A complex molecular program ensures that cells self-destruct in a controlled manner when they are no longer needed or severely damaged. Cancer cells can evade this mechanism and thus ensure their own survival, even those with genetic damage or targeted by a therapy," says Philipp Jost, a Med Uni Graz professor of oncology, describing an unusual feature of tumor cells.

The drug venetoclax shows that this mechanism can also be exploited therapeutically. It blocks the pro-survival protein BCL-2 and can trigger the programmed cell death of cancer cells in certain blood cancers. Today this approach is clinically established. However, tumor cells have several options for how they can evade programmed cell death. As a result, the focus of research is expanding beyond apoptosis to include other forms of cell death such as necroptosis, pyroptosis and ferroptosis.

Survival at any price as the Achilles heel of a cancer cell

Tumor cells have different mechanisms that protect them from programmed cell death. Which ones are critical to their survival depends, among other things, on their genetic characteristics. It is precisely these dependencies that could be targeted for use in cancer therapy.

"The critical question is what exactly keeps this tumor alive. If we know this dependency, we can selectively attempt to break through its protection against cell death," explains Jost.

One particularly exciting approach is ferroptosis. In this form of cell death, changes in iron and lipid metabolism result in damaging oxidation of the cell membrane. Cells are normally protected by the enzyme GPX4. Certain tumors might be particularly reliant on this protection. If the protective mechanism is blocked, cell death of the tumor cells can be triggered in experimental models. This approach has not been clinically established, yet it shows where research is headed. Tumors should be treated according to not only their organ of origin but increasingly their individual molecular dependencies.

The path to precision medicine

The selective triggering of ferroptosis has not been established as a cancer therapy. First of all, it is critical to identify the tumors that are actually dependent on specific mechanisms and at the same time to protect healthy tissue. This is precisely where modern cancer research comes in. Single-cell analysis, omics methods and CRISPR screens allow the individual survival strategies of tumor cells to be decoded with greater precision. "When we know this molecular dependency, we can selectively search for a therapeutic Achilles heel," says Jost.

Research at the Medical University of Graz is a combination of basic molecular research and the development of new therapeutic strategies. Jost leads a research team that focuses on molecular oncology and is substantially involved in investigating cell death mechanisms and their significance in cancer. Adam Wahida also conducts research in Jost's team and is the last author of the Cell publication. The long-term perspective is more personalized cancer therapy. Not every cancer cell should be targeted in the same way. Instead, the molecular basis of a tumor might help in making the decision of which cell death pathway to activate in therapy or what survival strategy to block.