2. Academic Validation
  3. Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models

Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models

  • Clin Cancer Res. 2024 Dec 30. doi: 10.1158/1078-0432.CCR-24-2807.
Sara Ortega-Bertran 1,  Juana Fernández-Rodríguez 2,  Miriam Magallón-Lorenz 3,  Xiaohu Zhang 4,  Edgar Creus-Bachiller 5,  Adriana Paola Diazgranados 6,  Itziar Uriarte-Arrazola 7,  Helena Mazuelas 3,  Ignacio Blanco 8,  Claudia Valverde 9,  Meritxell Carrió 3,  Alberto Villanueva 10,  Thomas De Raedt 11,  Cleofé Romagosa 12,  Bernat Gel 3,  Héctor Salvador 13,  Marc Ferrer 14,  Conxi Lázaro 15,  Eduard Serra 3
Affiliations

Affiliations

  • 1 Institut d'Investigació Biomédica de Bellvitge, Hospitalet de Llobregat, Spain.
  • 2 Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
  • 3 Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, Spain.
  • 4 National Center for Advancing Translational Sciences, Rockville, MD, United States.
  • 5 Institut d'Investigació Biomédica de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
  • 6 Vall d'Hebron Hospital Universitari, Spain.
  • 7 Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain.
  • 8 Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.
  • 9 Vall d'Hebron Hospital Universitari, Barcelona, Spain.
  • 10 Catalan Institute of Oncology (ICO/IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
  • 11 Children's Hospital of Philadelphia, Philadelphia, PA, United States.
  • 12 Vall d'Hebron Hospital Universitari, Barcelona, Barcelona, Spain.
  • 13 Hospital Sant Joan de Déu Barcelona, Spain.
  • 14 National Institutes of Health, Rockville, Maryland, United States.
  • 15 Institut Català d'Oncologia, L'Hospitalet del Llobregat, Barcelona, Spain.
PMID: 39786423 DOI: 10.1158/1078-0432.CCR-24-2807
Abstract

Purpose: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma that develops sporadically or in Neurofibromatosis type 1 patients. Its development is marked by the inactivation of specific tumor suppressor genes (TSGs): NF1, CDKN2A and SUZ12EED (Polycomb Repressor Complex 2). Each TSG loss can be targeted by particular drug inhibitors and we aimed to systematically combine these inhibitors, guided by TSG inactivation status, to test their precision medicine potential for MPNSTs.

Experimental design: We performed a high-throughput screening in three MPNST cell lines testing 14 MEK (MEKi), 11 CDK4/6 (CDKi) and 3 bromodomain (BETi) inhibitors as single agents and 147 pair-wise co-treatments. Best combinations were validated in 9 MPNST cell lines and three were tested in one sporadic and one NF1-associated patient-derived orthotopic xenograft (PDOX) MPNST mouse models. A final combination of the three inhibitor classes was tested in the same PDOX models.

Results: A high degree of redundancy was observed in the effect of compounds of the same inhibitory class, individually or in combination, and responses matched with TSG inactivation status. The MEKi-BETi (Arry-162+I-BET151) co-treatment triggered reduction of half of the NF1-related MPNST-PDOXs, and all the sporadic tumors, reaching 65% reduction in tumor volume in the latter. Remarkably, this reduction was further increased in both models combining the three inhibitor classes, reaching 85% shrinkage on average in the sporadic MPNST.

Conclusions: Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi-BETi-CDKi triple treatment elicits a significant reduction of human MPNST PDOX.

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