A study by the Mildred Scheel Early Career Center team led by Dr. Mohamed Elgendy at the TUD Medical School provides fundamental insights into cancer biology. Published in the prestigious journal Nature Communications, the study shows for the first time that the MCL1 protein not only inhibits programmed cell death, but also plays a central role in tumor metabolism.
The researchers were able to trace two classic hallmarks of cancer—avoidance of apoptosis (a form of programmed cell death) and dysregulation of energy metabolism—back to a common molecular mechanism.
The study focuses on the MCL1 protein, which is highly overexpressed in many tumor types and was previously thought to be primarily an anti-apoptotic factor of the Bcl-2 family of proteins. The Dresden researchers now show that MCL1 directly affects the central metabolic regulator mTOR and thus controls the bioenergetics of cancer cells. This is the first time that MCL1 has been described as an active regulator of central signaling and metabolic pathways.
“Our findings show that MCL1 is much more than just a survival factor for cancer cells,” says Dr. Mohamed Elgendy. “The protein actively interferes with key metabolic and developmental signaling pathways, thus linking two fundamental mechanisms of cancer.”
Mechanistically, the team identified a direct functional link between MCL1 and the mTORC1 complex in various cancer models. This newly discovered signaling pathway fundamentally expands the current understanding of the role of MCL1 and opens new therapeutic perspectives.
In addition to the genetic analyses, the study also investigated the effect of MCL1 inhibitors, which are currently in clinical development as promising new cancer therapeutics. The study showed that these agents also inhibit mTOR signaling. This finding is of high clinical importance, as mTOR inhibitors are already routinely used in cancer treatment.
Another particularly important finding is the resolution of a previously unsolved problem: several clinical trials with MCL1 inhibitors had to be stopped due to severe cardiotoxic side effects. Dresden researchers identified an underlying molecular mechanism for the first time and, based on this, developed a nutritional approach that can significantly reduce cardiac toxicity. This protective effect was confirmed in a novel humanized mouse model.
“This work represents a major advance in our understanding of the molecular basis of cancer,” says Prof. Esther Troost, Dean of the Carl Gustav Carus Medical School at TU Dresden. “This high-profile publication with enormous clinical potential proves once again that targeted support of outstanding young scientists, as realized at the Mildred Scheel Center for Young Scientists, is a prerequisite for tomorrow’s cancer innovations and treatment.”
Professor Uwe Platzbecker, Chief Medical Officer of the University Hospital Dresden, adds: “This outstanding research paper shows how excellent basic research can create immediate benefits for our cancer patients. Of particular clinical importance is the solution to the cardiotoxicity problem of MCL1 inhibitors.
The study is the result of interdisciplinary collaboration between various research groups and institutions. The working group of Dr. Mohamed Elgendy in Dresden acted as lead partner and was supported by experts from national and international partner institutions in the Czech Republic, Austria and Italy.
The importance of the work was also recognized by the editors of the journal Nature Communications: The publication was selected as one of the prominent cancer research papers on the “Editors’ Highlights” website, which presents the 50 best studies currently published in this field.
