CTPS1作为可靶向的脆弱性促进肺腺癌进展
CTPS1 promotes lung adenocarcinoma progression as a targetable vulnerability.
作者
作者单位
- Department of Thoracic Surgery, Tianjin Medical University Baodi Hospital, Tianjin, China.
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China.
- Beijing Pineal Diagnostics Co. Ltd., Beijing, China.
- Analysis Center, Chemistry Department, Tsinghua University, Beijing, China. whaosmith@mail.tsinghua.edu.cn.
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China. ecnuzdd@163.com.
- Department of Thoracic Surgery, Tianjin Medical University Baodi Hospital, Tianjin, China. wgsbdhospital@sina.com.
摘要
中文
胞苷三磷酸合成酶1（CTPS1）是核苷酸生物合成中的限速酶，在癌症中经常上调。然而，其在肺腺癌（LUAD）中的功能作用和治疗潜力仍不明确。我们整合了蛋白质组学分析、组织微阵列和功能测定，以评估CTPS1在LUAD中的表达和临床意义。使用选择性抑制剂STP938进行基因敲低和药理学抑制以评估恶性表型。在异种移植模型中评估了STP938单独或与奥希替尼联合的治疗效果。整合蛋白质组学和转录组学分析探讨了潜在机制。CTPS1在LUAD中显著上调，并与淋巴结转移和总生存期（OS）不良相关，是独立预后因素。CTPS1促进增殖、迁移和侵袭，同时抑制凋亡。STP938在体外和体内抑制肿瘤生长，并在EGFR突变模型中增强了奥希替尼的疗效。多组学分析确定MX1相关的干扰素信号传导为下游通路，MX1表达与CTPS1和不良预后呈正相关。CTPS1驱动LUAD进展，并与MX1相关的干扰素信号传导相关。使用STP938单独或联合奥希替尼靶向CTPS1代表了一种有前景的治疗策略，并支持CTPS1作为LUAD中可靶向的脆弱性。
English
Cytidine triphosphate synthase 1 (CTPS1), a rate-limiting enzyme in nucleotide biosynthesis, is frequently upregulated in cancers. However, its functional role and therapeutic potential in lung adenocarcinoma (LUAD) remain poorly defined. We integrated proteomic analyses, tissue microarrays, and functional assays to evaluate CTPS1 expression and clinical significance in LUAD. Genetic knockdown and pharmacological inhibition with the selective inhibitor STP938 assessed malignant phenotypes. The therapeutic efficacy of STP938, alone or combined with osimertinib, was evaluated in xenograft models. Integrated proteomic and transcriptomic analyses explored underlying mechanisms. CTPS1 was significantly upregulated in LUAD and associated with lymph node metastasis and poor overall survival (OS), serving as an independent prognostic factor. CTPS1 promoted proliferation, migration, and invasion while suppressing apoptosis. STP938 inhibited tumour growth in vitro and in vivo, and enhanced the efficacy of osimertinib in EGFR-mutant models. Multi-omics analyses identified MX1-associated interferon signalling as a downstream pathway, with MX1 expression positively correlating with CTPS1 and poor prognosis. CTPS1 drives LUAD progression and is linked to MX1-associated interferon signalling. Targeting CTPS1 with STP938, alone or in combination with osimertinib, represents a promising therapeutic strategy and supports CTPS1 as a targetable vulnerability in LUAD.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 7.8
- 新锐分区
- 1区