Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53-deficient myeloma cells.

Autor: Durand R; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Bellanger C; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Descamps G; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Dousset C; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Maïga S; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Derrien J; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Thirouard L; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Bouard L; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Asnagli H; Step Pharma Saint-Genis-Pouilly France., Beer P; Step Pharma Saint-Genis-Pouilly France., Parker A; Step Pharma Saint-Genis-Pouilly France., Gomez-Bougie P; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Devilder MC; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Moreau P; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Touzeau C; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Moreau-Aubry A; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Chiron D; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France., Pellat-Deceunynck C; Nantes Université, INSERM, CHU Nantes CNRS, Université d'Angers, CRCI2NA Nantes France.
Jazyk: angličtina
Zdroj: HemaSphere [Hemasphere] 2024 Oct 08; Vol. 8 (10), pp. e70016. Date of Electronic Publication: 2024 Oct 08 (Print Publication: 2024).
DOI: 10.1002/hem3.70016
Abstrakt: In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic TP53 gene inactivation is a high-risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53-deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 ( CTPS1 ), which encodes a CTP synthesis rate-limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high MKI67 expression) or a low p53 score (synonymous with TP53 deletion and/or mutation). This overexpression of CTPS1 was associated with reduced survival in two cohorts. Using scRNA-seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high CTPS1 expression. Pharmacological inhibition of CTPS1 by STP-B induced cell cycle arrest in early S phase in isogenic NCI-H929 or XG7 TP53 +/+ , TP53 -/- , and TP53 R175H/R175H cells and in a TP53 -/R123STOP patient sample. The functional annotation of transcriptional changes in 10 STP-B-treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP-B-induced S-phase arrested cells synergistically induced cell death in TP53 +/+ , TP53 -/- , and TP53 R175H/R175H isogenic cell lines (Bliss score >15). This combination induced replicative stress and caspase-mediated cell death and was highly effective in resistant/refractory patient samples with TP53 deletion and/or mutation and in TP53 -/- NCI-H929 xenografted NOD-scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53-deficient patients.
Competing Interests: Hélène Asnagli, Andrew Parker, and Philip Beer are employees of Step Pharma. The remaining authors declare no conflict of interest.
(© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)
Databáze: MEDLINE
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