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Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath
Sara Ortega-Bertran1,2,3, Juana Fernández-Rodríguez1,2,4,5, Miriam Magallón-Lorenz6
1Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
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.
Insights
Precision medicine for malignant peripheral nerve sheath tumors (MPNST) shows promise. Combining MEK, BET, and CDK inhibitors based on tumor suppressor gene status significantly shrinks MPNST tumors in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas.
- MPNST development involves inactivation of tumor suppressor genes (TSG) like NF1, CDKN2A, and SUZ12/EED.
- Targeting these TSG losses offers potential for precision therapies.
Purpose of the Study:
- To systematically combine drug inhibitors targeting specific TSG inactivation in MPNST.
- To evaluate the precision medicine potential of these drug combinations for MPNST treatment.
Main Methods:
- High-throughput screening of MEK inhibitors (MEKi), CDK inhibitors (CDKi), and BET inhibitors (BETi) in MPNST cell lines.
- Testing single agents and pairwise co-treatments, followed by validation in multiple cell lines and patient-derived xenograft (PDOX) models.
- Evaluating a triple combination of MEKi, BETi, and CDKi in MPNST PDOX models.
Main Results:
- Drug responses correlated with specific TSG inactivation status.
- MEKi-BETi combination reduced tumor volume in NF1-related and sporadic MPNST PDOX models.
- A triple combination of MEKi-BETi-CDKi achieved significant tumor shrinkage, averaging 85% in sporadic MPNST models.
Conclusions:
- MPNST treatment can be guided by TSG inactivation status, supporting precision therapies.
- The combination of MEK, BET, and CDK inhibitors demonstrates significant efficacy in reducing MPNST tumor burden in preclinical models.
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