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MULTIPLE MYELOMA, GAMMOPATHIES

CTPS1 is a novel therapeutic target in multiple myeloma which synergizes with inhibition of CHEK1, ATR or WEE1

Leukemia volume 38, pages 181–192 (2024)Cite this article

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Abstract

Targeting nucleotide biosynthesis is a proven strategy for the treatment of cancer but is limited by toxicity, reflecting the fundamental nucleotide requirement of dividing cells. The rate limiting step in de novo pyrimidine synthesis is of interest, being catalyzed by two homologous enzymes, CTP synthase 1 (CTPS1) and CTPS2, that could be differentially targeted. Herein, analyses of publicly available datasets identified an essential role for CTPS1 in multiple myeloma (MM), linking high expression of CTPS1 (but not CTPS2) with advanced disease and poor outcomes. In cellular experiments, CTPS1 knockout induced apoptosis of MM cell lines. Exposure of MM cells to STP-B, a novel and highly selective pharmacological inhibitor of CTPS1, inhibited proliferation, induced S phase arrest and led to cell death by apoptosis. Mechanistically, CTPS1 inhibition by STP-B activated DNA damage response (DDR) pathways and induced double-strand DNA breaks which accumulated in early S phase. Combination of STP-B with pharmacological inhibitors of key components of the DDR pathway (ATR, CHEK1 or WEE1) resulted in synergistic growth inhibition and early apoptosis. Taken together, these findings identify CTPS1 as a promising new target in MM, either alone or in combination with DDR pathway inhibition.

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Fig. 1: High CTPS1 expression is associated with disease progression and poor overall survival.
Fig. 2: MM cell lines depend on CTPS1 for proliferation.
Fig. 3: Selective CTPS1 inhibition by STP-B selectively impairs MM cell line viability and induces apoptosis.
Fig. 4: Selective CTPS1 inhibition by STP-B induces S phase cell cycle arrest and DNA damage.
Fig. 5: STP-B induces S phase cell cycle delay, replication stress and DNA damage in cells resistant to early inhibition of proliferation.
Fig. 6: STP-B synergizes with inhibitors of the DNA damage response (DDR) pathway.

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Data availability

The data analyzed in this study was obtained from Gene Expression Omnibus (GEO) at GSE9782, GSE2658, GSE6477, GSE19784 and GSE13591.

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Acknowledgements

The authors would like to thank Waltraud Scherbler and Pia Fritz (employees at Klinik Ottakring, Vienna, Austria), for their excellent technical support. This study was supported by the Austrian Forum against Cancer, the Österreichische Forschungsförderungsgesellschaft mbH (FFG, “Forschungspartnerschaften”), project number 878861 and a research grant from the Ingrid Shaker Nessmann (ISNK) Cancer Research Association given to AB; AS is a recipient of the DOC fellowship of the Austrian Academy of Science at the Wilhelminen Cancer Research Institute. In vivo studies conducted at Crown Bioscience were financed by Step Pharma.

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Author notes

  1. These authors contributed equally: Arnold Bolomsky, Philip A. Beer, Heinz Ludwig.

Authors and Affiliations

  1. Department of Medicine I, Klinik Ottakring, Wilhelminen Cancer Research Institute, Vienna, Austria

    Christina Pfeiffer, Anja Schneller, Julia Huber, Niklas Zojer, Arnold Bolomsky & Heinz Ludwig

  2. Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria

    Alexander M. Grandits

  3. Step Pharma, Saint-Genis-Pouilly, France

    Hélène Asnagli, Andrew E. Parker & Philip A. Beer

  4. Department of Medicine I, Center for Oncology and Hematology, Klinik Ottakring, Vienna, Austria

    Niklas Zojer & Martin Schreder

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Contributions

CP, AB, PAB and HL designed the study; CP performed the experiments, analyzed and interpreted data; AMG performed bioinformatics analysis of publicly available gene expression datasets; AB, AS, AMG, AEP, HA, JH, and PAB analyzed and interpreted data; NZ and MS interpreted data; CP and PAB. wrote the manuscript; HL provided funding, designed the study and supervised the research; all authors revised and approved the final version of the manuscript.

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Correspondence to Philip A. Beer or Heinz Ludwig.

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Competing interests

Philip A. Beer, Hélène Asnagli and Andrew E. Parker are employees of Step Pharma SAS. All other authors declare no conflict of interest.

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Pfeiffer, C., Grandits, A.M., Asnagli, H. et al. CTPS1 is a novel therapeutic target in multiple myeloma which synergizes with inhibition of CHEK1, ATR or WEE1. Leukemia 38, 181–192 (2024). https://doi.org/10.1038/s41375-023-02071-z

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