2026-04-17T01:26:27Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2220862025-12-10T01:10:06Zcom_2072_1057col_2072_478824col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Ortega Bertran, Sara author Fernández Rodríguez, Juana author Magallón Lorenz, Miriam author Zhang, Xiaohu author Creus Bachiller, Edgar author Diazgranados, Adriana Paola author Uriarte Arrazola, Itziar author Mazuelas, Helena author Blanco, Ignacio author Valverde Morales, Claudia author Carrió, Meritxell author Villanueva Garatachea, Alberto author Raedt, Thomas de author Romagosa Pérez-Portabella, Cleofé author Gel Moreno, Bernat author Salvador, Héctor author Ferrer, Marc author Lázaro García, Conxi author Serra Arenas, Eduard author 2025-07-08T09:22:39Z 2025-07-08T09:22:39Z 2025-03-03 2025-05-19T10:44:59Z Purpose: 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.Experimental Design: 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.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 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.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 PDOXs. Neurofibromatosi Neurofibromatosis Antioncogens Antioncogenes Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models