对 CTPS1 和 ATR 的联合抑制是 p53 缺陷骨髓瘤细胞的代谢弱点。

IF 7.6 2区 医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2024-10-08 DOI:10.1002/hem3.70016
Romane Durand, Céline Bellanger, Géraldine Descamps, Christelle Dousset, Sophie Maïga, Jennifer Derrien, Laura Thirouard, Louise Bouard, Hélène Asnagli, Philip Beer, Andrew Parker, Patricia Gomez-Bougie, Marie-Claire Devilder, Philippe Moreau, Cyrille Touzeau, Agnès Moreau-Aubry, David Chiron, Catherine Pellat-Deceunynck
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引用次数: 0

摘要

与 B 细胞恶性肿瘤一样,在多发性骨髓瘤中,单拷贝尤其是双拷贝 TP53 基因失活是导致耐药性的高危因素,目前还没有专门针对 p53 缺失的疗法。在本研究中,我们评估了 p53 缺失的骨髓瘤细胞失去细胞周期控制是否会带来代谢上的可操作性弱点。我们发现,CTP合成酶1(CTPS1)编码淋巴细胞DNA和RNA合成所必需的CTP合成限速酶,它在骨髓瘤患者高增殖率(MKI67高表达)或低p53评分(与TP53缺失和/或突变同义)样本中过度表达。在两个队列中,CTPS1 的过表达与生存率降低有关。通过对 24 例患者样本进行 scRNA-seq 分析,我们进一步证明骨髓瘤细胞在 S 期或 G2/M 期显示 CTPS1 的高表达。在同源的 NCI-H929 或 XG7 TP53 +/+、TP53 -/-、TP53 R175H/R175H 细胞以及 TP53 -/R123STOP 患者样本中,STP-B 对 CTPS1 的药理抑制诱导细胞周期停滞在早期 S 期。对 10 个 STP-B 处理过的骨髓瘤细胞系的转录变化进行的功能注释显示,蛋白质翻译减少,并证实细胞进入 S 期受阻。在STP-B诱导的S期停滞细胞中,药理学抑制ATR(控制内在S/G2检查点)可协同诱导TP53 +/+、TP53 -/-和TP53 R175H/R175H异源细胞系(Bliss评分>15)的细胞死亡。这种组合诱导复制应激和Caspase介导的细胞死亡,对TP53缺失和/或突变的耐药/难治性患者样本以及TP53 -/- NCI-H929异种移植NOD-scid IL2Rgamma小鼠非常有效。我们的体外、体内和体外数据为联合抑制 CTPS1 和 ATR 治疗 p53 缺失患者提供了理论依据。
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Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53-deficient myeloma cells

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 TP53R175H/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 TP53R175H/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.

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来源期刊
HemaSphere
HemaSphere Medicine-Hematology
CiteScore
6.10
自引率
4.50%
发文量
2776
审稿时长
7 weeks
期刊介绍: HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.
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