Article (Scientific journals)
Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma.
Cissé, Madi Y.; Pyrdziak, Samuel; Firmin, Nelly et al.
2020In Science Translational Medicine, 12 (547)
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Keywords :
Antineoplastic Agents/therapeutic use; Humans; Liposarcoma/drug therapy/genetics; Proto-Oncogene Proteins c-mdm2/metabolism; Serine/therapeutic use; Tumor Suppressor Protein p53/genetics
Abstract :
[en] Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Cissé, Madi Y.
Pyrdziak, Samuel
Firmin, Nelly
Gayte, Laurie
Heuillet, Maud
Bellvert, Floriant
Fuentes, Maryse
Delpech, Hélène
Riscal, Romain
Arena, Giuseppe ;  IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier F-34298, France.
Chibon, Frédéric
Le Gellec, Sophie
Maran-Gonzalez, Aurélie
Chateau, Marie-Christine
Theillet, Charles
Carrere, Sébastien
Portais, Jean-Charles
Le Cam, Laurent
Linares, Laetitia K.
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Title :
Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma.
Publication date :
Journal title :
Science Translational Medicine
Publisher :
American Association for the Advancement of Science, United States
Volume :
Issue :
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Commentary :
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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