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

Abstract

Combination of inhibitors; Peripheral nerve sheath; Mouse models

Combinació d'inhibidors; Beina del nervi perifèric; Models de ratolí

Combinación de inhibidores; Vaina del nervio periférico; Modelos de ratón

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.

We also wish to thank both pediatric and adult Spanish phakomatoses CSUR (Centros, Servicios y Unidades de Referencia) teams. This work has been supported mainly by Fundació la Marató de TV3 (51/C/2019). It has also been supported by the Carlos III National Institute of Health funded by FEDER funds—A Way to Build Europe (PI23/00017, PI23/00422, PI19/00553, and Centro de Investigación Biomédica en Red de Cáncer); the Department of Research and Universities of the Generalitat de Catalunya and AGAUR (Agència de Gestió d'Ajuts Universitaris i de Recerca; 2021SGR01112, 2021SGR00967); and Fundación Proyecto Neurofibromastosis. The publication/result/equipment/video/activity/contract/others is part of the project CPP2022-009550, funded by MCIU/AEI/10.13039/501100011033 and by the European Union “NextGenerationEU”/PRTR, with the institutional support provided by CERCA program/Generalitat of Catalunya.