High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition
Miriam Sartages,
Ebel Floridia,
Mar García-Colomer,
Cristina Iglesias,
Manuel Macía,
Patricia Peñas,
Pierre-Olivier Couraud,
Ignacio A. Romero,
Babette Weksler,
Celia M. Pombo,
Juan Zalvide
Affiliations
Miriam Sartages
Department of Physiology, Centro Singular de Medicina Molecular e Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15703 Santiago de Compostela, Spain
Ebel Floridia
Department of Physiology, Centro Singular de Medicina Molecular e Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15703 Santiago de Compostela, Spain
Mar García-Colomer
Department of Physiology, Centro Singular de Medicina Molecular e Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15703 Santiago de Compostela, Spain
Cristina Iglesias
Department of Physiology, Centro Singular de Medicina Molecular e Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15703 Santiago de Compostela, Spain
Manuel Macía
Servicio de Obstetricia y Ginecología Hospital Clínico Universitario Santiago, 15703 Santiago de Compostela, Spain
Patricia Peñas
Servicio de Obstetricia y Ginecología Hospital Clínico Universitario Santiago, 15703 Santiago de Compostela, Spain
Pierre-Olivier Couraud
INSERM, U1016, Institut Cochin, 22 Rue Mechain, 75014 Paris, France
Ignacio A. Romero
Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes MK7 6AA, UK
Babette Weksler
Weill Medical College, Cornell University, 1300 York Ave, New York, NY 10065, USA
Celia M. Pombo
Department of Physiology, Centro Singular de Medicina Molecular e Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15703 Santiago de Compostela, Spain
Juan Zalvide
Department of Physiology, Centro Singular de Medicina Molecular e Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15703 Santiago de Compostela, Spain
Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically.