Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models
Por:
Ortega-Bertran, S, Fernández-Rodríguez, J, Magallón-Lorenz, M, Zhang, XH, Creus-Bachiller, E, Diazgranados, AP, Uriarte-Arrazola, I, Mazuelas, H, Blancó, I, Valverde, C, Carrio, M, Villanueva, A, De Raedt, T, Romagosa, C, Gel, B, Salvador, H, Ferrer, M, Lázaro, C and Serra, E
Publicada:
3 mar 2025
Resumen:
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.
Filiaciones:
Ortega-Bertran, S:
Catalan Inst Oncol ICO IDIBELL, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Univ Barcelona, Doctoral Program Biomed, Barcelona, Spain
Fernández-Rodríguez, J:
Catalan Inst Oncol ICO IDIBELL, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
SCT IDIBELL, Mouse Lab, Barcelona, Spain
Magallón-Lorenz, M:
Germans Trias i Pujol Res Inst IGTP, Translat Canc Res Program, Hereditary Canc Grp, Can Ruti Campus, Badalona, Barcelona, Spain
Zhang, XH:
NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA
Creus-Bachiller, E:
Catalan Inst Oncol ICO IDIBELL, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Diazgranados, AP:
Hosp Univ Vall dHebron, Pathol Dept, Barcelona, Spain
Vall dHebron Res Inst VHIR, Barcelona, Spain
:
Germans Trias i Pujol Res Inst IGTP, Translat Canc Res Program, Hereditary Canc Grp, Can Ruti Campus, Badalona, Barcelona, Spain
:
Germans Trias i Pujol Res Inst IGTP, Translat Canc Res Program, Hereditary Canc Grp, Can Ruti Campus, Badalona, Barcelona, Spain
:
Hosp Badalona Germans Trias & Pujol, Clin Genet Dept, Lab Clin Metropolitana Nord, Barcelona, Spain
Valverde, C:
Hosp Univ Vall dHebron, Dept Med Oncol, Barcelona, Spain
Vall dHebron Inst Oncol, Barcelona, Spain
:
Germans Trias i Pujol Res Inst IGTP, Translat Canc Res Program, Hereditary Canc Grp, Can Ruti Campus, Badalona, Barcelona, Spain
Villanueva, A:
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Catalan Inst Oncol, Procure Program, Barcelona, Spain
De Raedt, T:
Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA USA
Univ Penn, Sch Med, Philadelphia, PA USA
Romagosa, C:
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Hosp Univ Vall dHebron, Pathol Dept, Barcelona, Spain
Vall dHebron Res Inst VHIR, Barcelona, Spain
:
Germans Trias i Pujol Res Inst IGTP, Translat Canc Res Program, Hereditary Canc Grp, Can Ruti Campus, Badalona, Barcelona, Spain
Univ Barcelona UB, Dept Fonaments Clin, Fac Med & Ciencies Salut, Barcelona, Spain
Salvador, H:
St Joan Deu Barcelona Childrens Hosp, Pediat Oncol Dept, Barcelona, Spain
Ferrer, M:
NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA
Lázaro, C:
Catalan Inst Oncol ICO IDIBELL, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol Oncobell, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
:
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Germans Trias i Pujol Res Inst IGTP, Translat Canc Res Program, Hereditary Canc Grp, Can Ruti Campus, Badalona, Barcelona, Spain
Green Submitted, hybrid
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