How the chemotherapy drug sorafenib triggers muscle wasting through cell remodeling

Chemotherapeutic agents are often used to treat cancer. They combat tumor growth, but also have a number of undesirable side effects. One of these is severe muscle wasting, known as chemotherapy-induced cachexia. This chronic disease causes uncontrollable breakdown of fat and muscle tissue as well as weight loss. However, in order to improve treatment strategies, the molecular basis must first be understood.

This is where PD Dr. Arnab Nayak, a scientist at the Institute of Molecular and Cellular Physiology at Hannover Medical School (MHH), comes in. With his research group “Chromatin and SUMO Physiology,” the molecular biologist has shown that the chemotherapeutic agent sorafenib actively remodels skeletal muscle cells and thus triggers cachexia. The work has been published in the journal iScience.

Formation and function of skeletal muscle fibers impaired

Sorafenib is used for liver cell carcinoma (HCC) and renal cell carcinoma (RCC), among others. The chemotherapeutic agent belongs to the so-called tyrosine kinase inhibitors, which attack chemical messengers that are important for tumor development.

Sorafenib targets several enzymes involved in cell growth as well as the formation of new blood vessels triggered by the tumor itself, which tumors use to ensure their supply of oxygen and nutrients. At the same time, sorafenib interferes with epigenetic regulation in muscle-specific genes. “Epigenetics” describes mechanisms that do not influence the genes themselves, but their activity.

In this way, epigenetic processes control which genes are switched on or off and therefore also have an influence on whether and when a disease breaks out or not. Through epigenetic mechanisms, cells react to environmental influences, among other things.

In the case of sorafenib, the researchers have uncovered an unusual molecular mechanism in transcription, ie, in the reading of the DNA sections relevant to the muscle fibers and their transfer into the corresponding blueprint.

In the case of sorafenib, the researchers have uncovered an unusual molecular mechanism in transcription, ie, in the reading of the DNA sections relevant to the muscle fibers and their transfer into the corresponding blueprint. This leads to impaired development of the skeletal muscle fibers.

Basis for therapeutic fine-tuning

The researchers also investigated the drugs nilotinib and imatinib, which belong to the same class of chemotherapeutic agents. Nilotinib is used in particular for chronic lymphocytic leukemia (CLL), while imatinib is used to treat acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumors (GIST).

“Interestingly, these two tyrosine kinase inhibitors did not show a similar effect on muscle cell function,” says Dr. Nayak. According to the cell biologist, the critical evaluation of cancer-specific chemotherapeutic agents with regard to their effects on muscle physiology is the key to developing better therapies.

“The detailed findings from our study provide the background and framework for similar future investigations to fine-tune chemotherapeutic treatment. The correct selection of drugs with minimal side effects or potentially harmful effects that can be counteracted is only possible with knowledge of the underlying affected signaling pathways.

Therefore, the implications of these findings for the development of balanced combination therapies for affected individuals to improve treatment are of immediate importance. However, sorafenib is currently one of the best therapeutics for the treatment of HCC and RCC.

“However, our findings have the potential to develop new therapeutic regimens to minimize chemotherapy-induced cachexia,” says Dr. Nayak.

Provided by Medizinische Hochschule Hannover