ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Review
- Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities.Nature communications · 2026Article
- MAPK-dependent release of GDNF from Schwann cells mediates tumor-independent pain in neurofibromatosis 1.Science signaling · 2026Article
- Ex Vivo Characterization Studies Identify Candidate Therapies for the Individualized Care ofCancers · 2026Article
- Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling.PLoS genetics · 2026Article
- Article
- Personalized medicine strategy for MPNSTs: using precision oncology on PDOX models to inform tumor boards.Journal of translational medicine · 2026Article
- Neurofibromatosis Type 1 and the Search for Effective Tumor Therapies Using High-Throughput Drug Screening.Current oncology (Toronto, Ont.) · 2025Review
- New models for MPNST: establishment and comprehensive characterization of two tumor cell lines.Cancer cell international · 2025Article
- Bromodomain and extra-terminal proteins in solid tumors: regulators of immune microenvironment and emerging therapeutic targets.Frontiers in immunology · 2025Review
- MAPK-targeted therapies in non-gastrointestinal stromal tumor soft tissue sarcomas: current landscape and future directions.Frontiers in oncology · 2025Review
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Authors and funding
19 authors.
Funding
Abstract
purposeMalignant 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
designWe 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.
resultsA 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.
conclusionsOur 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.