MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ

Sandra Schrenk, Lindsay J. Bischoff, Jillian Goines, Yuqi Cai, Shruti Vemaraju, Yoshinobu Odaka, Samantha R. Good, Joseph S. Palumbo, Sara Szabo, Damien Reynaud, Catherine D. Raamsdonk, Richard A. Lang and Elisa Boscolo ()
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Sandra Schrenk: Cincinnati Children’s Hospital Medical Center
Lindsay J. Bischoff: Cincinnati Children’s Hospital Medical Center
Jillian Goines: Cincinnati Children’s Hospital Medical Center
Yuqi Cai: Cincinnati Children’s Hospital Medical Center
Shruti Vemaraju: Cincinnati Children’s Hospital Medical Center
Yoshinobu Odaka: Cincinnati Children’s Hospital Medical Center
Samantha R. Good: Cincinnati Children’s Hospital Medical Center
Joseph S. Palumbo: University of Cincinnati College of Medicine
Sara Szabo: Cincinnati Children’s Hospital Medical Center
Damien Reynaud: Cincinnati Children’s Hospital Medical Center
Catherine D. Raamsdonk: University of British Columbia
Richard A. Lang: Cincinnati Children’s Hospital Medical Center
Elisa Boscolo: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Activating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences of GNAQ mutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutant GNAQ in endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival.

Date: 2023
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DOI: 10.1038/s41467-023-37516-7

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