Aside from their intended effects on cancer cells, anticancer drugs often cause severe and sometimes painful side effects including a loss of hair, nausea and immune system depression. Additionally, many patients suffer from a tingling of the hands or much more severe nervous problems, such as loss of their sense of touch. Others complain of heightened sensitivity to light (photosensitivity); any of these symptoms can severely affect a patient’s quality of life. One reason for side effects lies in the mode of action of these drugs: Many of them attack not only quite specific proteins in cancer cells, their intended targets, but other proteins in healthy cells as well. While in some cases these secondary effects may boost the desired effect of a drug, the typical results are adverse side effects. Identifying the unintentional targets of a new drug in advance might make it possible to predict undesirable side effects. It would help clinicians estimate not only whether, but especially why and how they might occur.
A team of scientists from the company Cellzome in Heidelberg and the Swedish Karolinska Institute, collaborating with Professor Bernhard Küster of Technische Universität München at the DKTK partnering site in Munich, have now used a simple but sophisticated method to make such predictions. By heating leukemia cells to temperatures between 40°C and 70°C, the scientists were able to identify new target proteins of anticancer drugs. The heat caused cellular proteins to start “melting”. “Each individual protein in a cell has a characteristic melting behavior, which we can measure,” says Dr Mikhail Savitski, the first author of the study. “When we administer anticancer drugs into cells, the drugs bind to specific proteins and modify them. These changes also affect their melting behavior, which we can measure again.”
Ideally, drugs should bind only to the specific proteins they are meant to target. However, in most cases they also bind to other proteins – usually not only molecules found in tumor cells, but in healthy ones as well. This is usually the cause of side effects. The scientists used protein mass spectroscopy to track these changes in the melting behavior of proteins in living cells. “We can thus exactly determine the effects of a drug,” Küster says. “We hope to use this method in the future to explain or even predict many adverse effects.” Küster is head of the participating research group at the DKTK partnering site of Technische Universität München.
In the current study, the researchers used the new method in an examination of a number of anticancer drugs. The list included vemurafenib, an agent that is used primarily to treat melanoma skin cancer. It was originally developed as an inhibitor of a cancer protein called B-Raf. However, in many patients it also causes painful photosensitivity that has an adverse effect on their quality of life. The new method allowed the scientists to discover a new, unexpected target of this agent: an enzyme called ferrochelatase. This enzyme is required for the production of heme, the red pigment component of hemoglobin. When vemurafenib is administered in healthy cells, the ferrochelatase enzyme ceases to function – an effect which can be measured based on its melting behavior. This loss of function is known from another condition called cutaneous porphyria, an inherited metabolic disorder that leads to extreme and painful photosensitivity of the skin. Patients who suffer from this disorder exhibit the same defect in the enzyme. So the finding will have immediate clinical benefits, which gives Küster reason for hope: “Thanks to our results it should be possible to develop new agents that no longer bind to the ferrochelatase enzyme, which will relieve patients from the fear of photosensitivity as an adverse effect of anticancer drugs.”
Mikhail Savitski, Friedrich Reinhard, Holger Franken, Thilo Werner, Maria Fälth Savitski, Dirk Eberhard, Daniel Molina, Rozbeh Jafari, Rebecca Bakszt Dovega, Susan Klaeger, Bernhard Kuster, Pär Nordlund, Marcus Bantscheff, Gerard Drewes: Tracking cancer drugs in living cells by thermal profiling of the proteome. Science 2014. DOI 10.1126/science.1255784.
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.