Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma

Madi Cissé (1, 2) , Samuel Pyrdziak (1, 2) , Nelly Firmin (1, 2, 3) , Laurie Gayte (1, 2) , Maud Heuillet (4, 5) , Floriant Bellvert (4, 5) , Maryse Fuentes (1, 2) , Hélène Delpech (1, 2) , Romain Riscal (1, 2) , Giuseppe Arena (1, 2) , Frédéric Chibon (6) , Sophie Le Gellec (6, 7) , Aurélie Maran-Gonzalez (3) , Marie-Christine Chateau (3) , Charles Theillet (1, 2) , Sébastien Carrere (1, 2, 3) , Jean-Charles Portais (4, 5) , Laurent Le Cam (1, 2) , Laetitia Linares (1, 2)

1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
2 Equipe labelisée Ligue Contre le Cancer
3 ICM - UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle
4 TBI - Toulouse Biotechnology Institute
5 MetaboHUB-MetaToul
6 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
7 Institut Claudius Regaud

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.

Domaines: Médecine humaine et pathologie

Madi Cissé, Samuel Pyrdziak, Nelly Firmin, Laurie Gayte, Maud Heuillet, et al.. Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma. Science Translational Medicine, 2020, 12 (547), ⟨10.1126/scitranslmed.aay2163⟩. ⟨hal-03436075⟩