Supplementary Figure S1 from Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models

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

doi:10.1158/1078-0432.28523172

Supplementary Figure S1 from Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models

journal contribution

posted on 2025-03-03, 08:40 authored by Sara Ortega-Bertran, Juana Fernández-Rodríguez, Miriam Magallón-Lorenz, Xiaohu Zhang, Edgar Creus-Bachiller, Adriana Paola Diazgranados, Itziar Uriarte-Arrazola, Helena Mazuelas, Ignacio Blanco, Claudia Valverde, Meritxell Carrió, Alberto Villanueva, Thomas De Raedt, Cleofé Romagosa, Bernat Gel, Héctor Salvador, Marc Ferrer, Conxi Lázaro, Eduard Serra

Dose response curves for all 28 single inhibitors in three independent MPNST cell lines

Funding

Fundació la Marató de TV3 (Fundació la Marató)

Instituto de Salud Carlos III (ISCIII)

Generalitat de Catalunya (Government of Catalonia)

Ministerio de Ciencia, Innovación y Universidades (MCIU)

History

ARTICLE ABSTRACT

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.