Ortega-Bertran Sara, Fernández-Rodríguez Juana, Magallón-Lorenz Miriam, Zhang Xiaohu, Creus-Bachiller Edgar, Diazgranados Adriana Paola, Uriarte-Arrazola Itziar, Mazuelas Helena, Blanco Ignacio, Valverde Claudia, Carrió Meritxell, Villanueva Alberto, De Raedt Thomas, Romagosa Cleofé, Gel Bernat, Salvador Héctor, Ferrer Marc, Lázaro Conxi, Serra Eduard
Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Clin Cancer Res. 2025 Mar 3;31(5):907-920. doi: 10.1158/1078-0432.CCR-24-2807.
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft-tissue sarcoma that develops sporadically or in patients with neurofibromatosis type 1 (NF1). Its development is marked by the inactivation of specific tumor suppressor genes (TSG): NF1, CDKN2A, and SUZ12/EED (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.
We performed a high-throughput screening in 3 MPNST cell lines testing 14 MEK inhibitors (MEKi), 11 cyclin-dependent kinase 4/6 inhibitors (CDKi), and 3 bromodomain inhibitors (BETi) as single agents and 147 pairwise co-treatments. Best combinations were validated in nine MPNST cell lines, and three were tested in one sporadic and one NF1-associated patient-derived orthotopic xenograft (PDOX) MPNST mouse model. A final combination of the three inhibitor classes was tested in the same PDOX models.
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 a reduction in 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.
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 PDOXs.
恶性外周神经鞘瘤（MPNST）是一种侵袭性软组织肉瘤，可散发发生或在1型神经纤维瘤病（NF1）患者中发生。其发展的特征是特定肿瘤抑制基因（TSG）失活：NF1、CDKN2A和SUZ12/EED（多梳抑制复合物2）。每种TSG缺失都可以被特定的药物抑制剂靶向，我们旨在以TSG失活状态为指导，系统地联合这些抑制剂，以测试它们对MPNST的精准医疗潜力。
我们在3种MPNST细胞系中进行了高通量筛选，测试了14种MEK抑制剂（MEKi）、11种细胞周期蛋白依赖性激酶4/6抑制剂（CDKi）和3种溴结构域抑制剂（BETi）作为单一药物以及147种两两联合治疗。最佳组合在9种MPNST细胞系中得到验证，其中3种在1例散发型和1例NF1相关的患者来源原位异种移植（PDOX）MPNST小鼠模型中进行了测试。在相同的PDOX模型中测试了三种抑制剂类别的最终组合。
在同一抑制类别化合物单独或联合使用的效果中观察到高度冗余，且反应与TSG失活状态相匹配。MEKi-BETi（ARRY-162 + I-BET151）联合治疗使一半的NF1相关MPNST PDOX和所有散发性肿瘤缩小，后者肿瘤体积减少65%。值得注意的是，在两种模型中，将三种抑制剂类别联合使用时，这种缩小进一步增加，散发性MPNST平均缩小85%。
我们的结果有力地支持了以TSG失活状态为指导的MPNST精准治疗。MEKi-BETi CDKi三联疗法可显著减少人MPNST PDOX。
