2. Academic Validation
  3. The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart

The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart

  • bioRxiv. 2025 Sep 8:2025.09.05.671511. doi: 10.1101/2025.09.05.671511.
Kelsey H Fisher-Wellman 1,  Richard D Lutze 2,  Logan G Kirkland 2,  Ju Youn Beak 2,  Samantha M Morrissey 3,  Peyton B Sandroni 2 3,  Wei Huang 2,  Julian D Bailon 2,  Melissa A Schroder 2,  Lars A Albrecht 2,  Mansi Goyal 2,  Andrew L Chin 2,  Thomas D Green 4,  Joseph M McClung 4,  McLane M Montgomery 5,  James T Hagen 5,  Brett R Chrest 5,  Jon S Zawistowski 6,  Timothy J Stuhlmiller 6,  Shawn M Gomez 6,  Nanthip Prathumsap 7 8,  Qing Zhang 9,  Jing Zhang 10,  Weiyi Xu 11,  Lilei Zhang 11,  Jeremy A Meier 12,  Lisa A Carey 12,  Jonathan C Schisler 2 6,  Gary L Johnson 6 12,  Brian C Jensen 2 6 13
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC.
  • 2 University of North Carolina McAllister Heart Institute, Chapel Hill, NC.
  • 3 University of North Carolina School of Medicine, Department of Medicine.
  • 4 Section of Molecular Medicine, Department of Internal Medicine and Department of Vascular and Endovascular Surgery, Wake Forest University School of Medicine.
  • 5 Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.
  • 6 University of North Carolina School of Medicine, Department of Pharmacology.
  • 7 Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Dusit, Bangkok 10300, Thailand.
  • 8 Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 9 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.
  • 10 Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 11 Department of Molecular & Human Genetics, Baylor College of Medicine.
  • 12 University of North Carolina, Lineberger Comprehensive Cancer Center.
  • 13 University of North Carolina School of Medicine, Division of Cardiology.
PMID: 40964318 DOI: 10.1101/2025.09.05.671511
Abstract

Trametinib (Trm) is a highly selective MEK Inhibitor that potently and persistently abrogates ERK1/2 activation. Trm initially was used to treat BRAF V600E-mutated melanoma but its FDA-approved indications are expanding rapidly. Trm generally is well tolerated but it can cause dose-limiting cardiomyopathy and heart failure. Here we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some Cancer cell types. In vivo, Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part through blunted activity of Electron Transport System Complexes. Trm-mediated mitochondrial injury led to the release of mitochondrial Damage-Associated Molecular Patterns including mitochondrial DNA in both mice and humans, triggering activation of canonical innate immune pathways including cGAS-STING. In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations but this lesion was reversed by expression of a phosphomimetic STAT3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all Cancer cell lines, identifying a previously unrecognized effect that could contribute to Trm's anti-cancer efficacy.

Keywords

Animal models of human disease; basic science research; cell signaling/signal transduction; mechanisms; proteomics; translational studies.

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