MEK/MELK inhibition and blood-brain barrier deficiencies in atypical teratoid/rhabdoid tumors

Michael H. Meel, Miriam Guillén Navarro, Mark C. de Gooijer, Dennis S. Metselaar, Piotr Waranecki, Marjolein Breur, Tonny Lagerweij, Laurine E. Wedekind, Jan Koster, Marianne D. van de Wetering, Netteke Schouten-van Meeteren, Eleanora Aronica, Olaf van Tellingen, Marianna Bugiani, Timothy N. Phoenix, Gertjan J.L. Kaspers, Esther Hulleman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

18 Citaten (Scopus)


Background: Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signaling axis and preclinical antitumor efficacy of its inhibition have been described in AT/RT.

Methods: We established and validated a patient-derived neurosphere culture and xenograft model of sonic hedgehog (SHH) subtype AT/RT, at diagnosis and relapse from the same patient. We set out to study the vascular phenotype of these tumors to evaluate the integrity of the blood-brain barrier (BBB) in AT/RT. We also used the model to study combined mitogen-activated protein kinase kinase (MEK) and maternal embryonic leucine zipper kinase (MELK) inhibition as a therapeutic strategy for AT/RT.

Results: We found MELK to be highly overexpressed in both patient samples of AT/RT and our primary cultures and xenografts. We identified a potent antitumor efficacy of the MELK inhibitor OTSSP167, as well as strong synergy with the MEK inhibitor trametinib, against primary AT/RT neurospheres. Additionally, vascular phenotyping of AT/RT patient material and xenografts revealed significant BBB aberrancies in these tumors. Finally, we show in vivo efficacy of the non-BBB penetrable drugs OTSSP167 and trametinib in AT/RT xenografts, demonstrating the therapeutic implications of the observed BBB deficiencies and validating MEK/MELK inhibition as a potential treatment.

Conclusion: Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.
Originele taal-2Engels
Pagina's (van-tot)58-69
Aantal pagina's12
Nummer van het tijdschrift1
StatusGepubliceerd - 11 jan. 2020


  • atypical teratoid/rhabdoid tumor
  • blood-brain barrier
  • maternal embryonic leucine zipper kinase
  • preclinical therapy development
  • tumor models

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