The iron-dependent cell death ferroptosis and the cell death caused by oxidative stress can be activated in small cell lung cancer and induced by two drugs.
A research team led by biologist Dr. Silvia von Karstedt has discovered two new ways to induce tumor cell death when examining samples of small cell lung tumors. One of two subtypes of tumor cells can be combated by activating ferroptosis, the iron-dependent cell death caused by oxidative stress. In the second subtype, oxidative stress - and associated cell death - can also be induced in an alternative way. Both types of cell death must be triggered simultaneously by drugs in order to kill as many tumor cells as possible. The results of the study were published in the journal Nature Communications.
Despite many advances in treatment, the diagnosis of small cell lung cancer means a particularly poor prognosis. In Germany, there are up to 8,000 new cases of small cell lung cancer (SCLC) every year. When cancer is discovered, it has already found many loopholes to escape the body's immune system. The classic cell death mechanisms, such as regulated cell death through apoptosis, are usually already inactivated. The tumor cells can therefore continue to divide and spread almost uncontrolled.
Characteristic for small cell lung cancer is a high cell division rate, which initially promises a good response to chemotherapy. "Unfortunately, in many cases the success of chemotherapy only lasts for a short time, as the tumor cells develop resistance to the therapy. In addition, a tumor consists not only of one but of different cell types, the so-called subtypes, which try to escape the lethal therapy in different ways," says von Karstedt, research group leader at the Cluster of Excellence for Ageing Research (CECAD), the Department of Translational Genomics at the University of Cologne and the Centre for Molecular Medicine Cologne (CMMC). This is where her research comes in. The biologist is trying to understand which cell death mechanisms in the cancer cells are already inactivated and which can still be used by a targeted therapy to kill the tumor.
The starting material for the study were patient samples taken at the time of diagnosis and thus depicting the still untreated tumor. In order to find out which paths to cell death are still possible, the research group compared the gene activity between patient cells taken from inside and outside the tumor. The signalling pathways important for the classical cell death mechanisms were already switched off inside the tumor at this early stage before therapy. In contrast, genes important for the activation of iron-dependent cell death through oxidative damage (ferroptosis) were strongly activated in the cancer cells.
Simplified, the cells of small cell lung cancer can be divided into two subtypes: The neuroendocrine cells and non-neuroendocrine cells. In the subgroup of neuroendocrine cells, more genes are active that are otherwise typically found in nerve cells that produce hormones. The cells of the other subtype do not have this characteristic and are therefore grouped together as non-neuroendocrine cells. "We were able to show in various experiments that cells of the non-neuroendocrine type can be induced to die with the help of buthionine sulfoximine, which triggers ferroptosis. In cells belonging to the neuroendocrine subtype, we found that they protect themselves from oxidative stress and thus from cell death with the production of antioxidants. However, by adding the antioxidant inhibitor auranofin, we were also able to kill these cells," explains PhD student Christina Bebber, the first author of the paper.
With regard to a possible application of these findings for the therapy of small cell lung cancer, the biologists made an important observation: If they attacked a tumor consisting of cells of both subtypes by only one of the two pathways - i.e. either switching on ferroptosis or inhibiting antioxidant production - the cancer cells were able to avoid the lethal therapy. They adjusted their gene expression to switch to the subtype that could resist the particular attack. "By using the combination therapy, we deprived the tumor cells of this escape route. What is also special about the study is that we used drugs that have already been investigated in extensive clinical trials or even approved for another area of application," explains von Karstedt.
The active substance buthionine sulfoximine, which triggers ferroptosis, is already being investigated in clinical trials in cancer therapy. The gold salt auranofin, which blocks the formation of protective antioxidants, has been approved for decades for the treatment of rheumatoid arthritis. Future clinical trials of a combined therapy will clarify to what extent this targeted therapy option will improve the prognosis of a small cell lung cancer diagnosis.
Bebber, C.M., Thomas, E.S., Stroh, J. et al. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nat Commun 12, 2048 (2021). https://doi.org/10.1038/s41467-021-22336-4