Reframing the role of MCL1 in cancer signaling and metabolism

A study by the Mildred Scheel Early Career Center group led by Dr. Mohamed Elgendy at the TUD Faculty of Medicine provides fundamental insights into cancer biology. Published in the renowned journal Nature Communications, the study shows for the first time that the protein MCL1 not only inhibits programmed cell death, but also plays a central role in tumor metabolism.

The researchers have succeeded in tracing two classic hallmarks of cancer – the evasion of apoptosis (a form of programmed cell death) and the dysregulation of energy metabolism – back to a common molecular mechanism.

The study focuses on the protein MCL1, which is strongly overexpressed in many tumor types and has previously been considered primarily an anti-apoptotic factor of the Bcl-2 protein family. The Dresden researchers now show that MCL1 directly influences 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 tumor cells," says Dr. Mohamed Elgendy. "The protein actively intervenes in key metabolic and growth signaling pathways, thereby linking two fundamental cancer mechanisms."

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 up new therapeutic perspectives.

In addition to genetic analyses, the study also investigated the effect of MCL1 inhibitors, which are currently undergoing clinical development as promising new cancer therapeutics. The study showed that these agents also inhibit mTOR signaling. This finding is of high clinical relevance, as mTOR inhibitors are already routinely used in cancer therapy.

Another particularly significant finding is the resolution of a previously unsolved problem: several clinical trials with MCL1 inhibitors had to be discontinued due to severe cardiotoxic side effects. The Dresden researchers identified an underlying molecular mechanism for the first time and, based on this, developed a dietary approach that can significantly reduce cardiac toxicity. This protective effect was confirmed in an innovative humanized mouse model.

"This work represents a significant advance in our understanding of the molecular basis of cancer," says Prof. Esther Troost, Dean of the Carl Gustav Carus Faculty of Medicine at TU Dresden. "This high-ranking publication with enormous clinical potential once again demonstrates that the targeted support of outstanding young scientists, as carried out at the Mildred Scheel Center for Young Scientists, is a prerequisite for innovations and the cancer therapy of tomorrow."

Prof. Uwe Platzbecker, Chief Medical Officer of the University Hospital Dresden, adds: "This outstanding research work exemplifies how excellent basic research can create direct benefits for our cancer patients. Particularly significant from a clinical perspective is the solution to the cardiotoxicity problem of MCL1 inhibitors. The identification of the underlying mechanism and the development of a dietary protective approach can now pave the way for safer therapies."

The study is the result of interdisciplinary collaboration between various research groups and institutions. Dr. Mohamed Elgendy's working group in Dresden acted as the lead partner and was supported by experts from national and international partner institutes in Czechia, 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 outstanding research papers on cancer on the "Editors' Highlights" website, which presents the 50 best currently published studies in this field.