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In this study, we evaluated if the loss of cell cycle control in p53\u2010deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (\n                    <jats:italic>CTPS1<\/jats:italic>\n                    ), which encodes a CTP synthesis rate\u2010limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high\n                    <jats:italic>MKI67<\/jats:italic>\n                    expression) or a low p53 score (synonymous with\n                    <jats:italic>TP53<\/jats:italic>\n                    deletion and\/or mutation). This overexpression of\n                    <jats:italic>CTPS1<\/jats:italic>\n                    was associated with reduced survival in two cohorts. Using scRNA\u2010seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2\/M phase display high\n                    <jats:italic>CTPS1<\/jats:italic>\n                    expression. Pharmacological inhibition of CTPS1 by STP\u2010B induced cell cycle arrest in early S phase in isogenic NCI\u2010H929 or XG7\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    ,\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    , and\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>R175H\/R175H<\/jats:sup>\n                    cells and in a\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\u2212\/R123STOP<\/jats:sup>\n                    patient sample. The functional annotation of transcriptional changes in 10 STP\u2010B\u2010treated 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\u2010B\u2010induced S\u2010phase arrested cells synergistically induced cell death in\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    ,\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    , and\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>R175H\/R175H<\/jats:sup>\n                    isogenic cell lines (Bliss score &gt;15). This combination induced replicative stress and caspase\u2010mediated cell death and was highly effective in resistant\/refractory patient samples with\n                    <jats:italic>TP53<\/jats:italic>\n                    deletion and\/or mutation and in\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    NCI\u2010H929 xenografted NOD\u2010scid 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\u2010deficient patients.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70016","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T19:40:27Z","timestamp":1728416427000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53\u2010deficient myeloma cells"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5422-0362","authenticated-orcid":false,"given":"Romane","family":"Durand","sequence":"first","affiliation":[{"name":"Nantes Universit\u00e9, INSERM, CHU Nantes CNRS, Universit\u00e9 d'Angers, CRCI2NA Nantes 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