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

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.