Researchers in Dresden have discovered that the protein MCL1, known for helping cancer cells evade death, also regulates their energy production through the mTOR pathway. This dual role explains why drugs targeting MCL1 can fight tumors but sometimes harm the heart. The team has developed a dietary approach to mitigate this cardiotoxicity, paving the way for safer therapies.
Cancer cells thrive by avoiding programmed cell death, or apoptosis, and by rewiring their metabolism to fuel rapid growth. A study led by Dr. Mohamed Elgendy at Technische Universität Dresden reveals that these two hallmarks are interconnected through the protein MCL1.
MCL1, part of the Bcl-2 family, is overexpressed in many tumors and was previously seen mainly as an anti-death agent. The researchers found that it directly influences the mTORC1 complex, a key controller of cellular energy and growth. "Our findings show that MCL1 is much more than just a survival factor for tumor cells," Dr. Elgendy said. "The protein actively intervenes in key metabolic and growth signaling pathways, thereby linking two fundamental cancer mechanisms."
Using various cancer models, the team confirmed this MCL1-mTOR link. Importantly, inhibitors of MCL1, which are in clinical trials, also dampen mTOR signaling—overlapping with existing mTOR-targeted cancer drugs.
A major hurdle for these inhibitors has been severe heart damage observed in trials, leading to their suspension. For the first time, the Dresden group pinpointed the molecular basis of this cardiotoxicity. They devised a dietary strategy that substantially lessened heart injury, validated in a humanized mouse model.
"This work represents a significant advance in our understanding of the molecular basis of cancer," noted Prof. Esther Troost, Dean of the Carl Gustav Carus Faculty of Medicine at TU Dresden. Prof. Uwe Platzbecker, Chief Medical Officer of University Hospital Dresden, highlighted the clinical promise: "Particularly significant... is the solution to the cardiotoxicity problem of MCL1 inhibitors."
The collaborative effort involved partners from Czechia, Austria, and Italy. Published in Nature Communications in 2025, the paper earned a spot in the journal's Editors' Highlights for cancer research.
