Comprehensive analysis of a real-world cohort identifies geranylgeranyl diphosphate synthase 1 as a predictor of chemoresistance in small cell lung cancer.

IF 5.7 2区 医学 Q1 ONCOLOGY
Yi Deng, Chenchen Guo, Tengfei Zhang, Yuan Chen, Xin Zhang, Hongbin Ji, Liang Hu
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引用次数: 0

Abstract

A subset of patients with small cell lung cancer (SCLC) exhibit intrinsic resistance to chemotherapy. However, biomarkers that effectively predict this group of patients are still lacking. We previously reported that high geranylgeranyl diphosphate synthase 1 (GGPS1) expression is associated with poor overall survival (OS) in SCLC, and statin combination therapy is effective in overcoming chemoresistance, especially in GGPP-high SCLC. However, the expression patterns of GGPS1 in SCLC subtypes and its relationship with clinical chemotherapy response remain unclear, and whether GGPS1 indicates statin treatment sensitivity in chemoresistant SCLC needs further validation. Through integrative analyses of 146 real-world SCLC cases, we found that approximately 25% exhibited high GGPS1 expression. Subgroup analysis revealed that GGPS1 expression was higher in the ASCL1/NEUROD1/POU2F3 triple-negative subgroup. Moreover, high GGPS1 expression was significantly correlated with reduced objective response rate (ORR) and progression-free survival (PFS) as well as OS. In addition, analysis of seven paired biopsy samples demonstrated that GGPS1 was upregulated in chemoresistant SCLC. We further showed that the combination of etoposide and cisplatin (E/P) with statins had improved efficacy in a patient-derived xenograft (PDX) model derived from a relapsed patient with high GGPS1 expression. Our findings suggest that GGPS1 is a promising biomarker for predicting chemoresistance in SCLC and may be a potential indicator of sensitivity to statin combination therapy in chemoresistant SCLC.

一项真实世界队列的综合分析确定香叶二磷酸合成酶1是小细胞肺癌化疗耐药的预测因子。
一小部分小细胞肺癌(SCLC)患者表现出对化疗的内在耐药性。然而,有效预测这组患者的生物标志物仍然缺乏。我们之前报道了高表达的香叶二磷酸合成酶1 (GGPS1)与SCLC的总生存期(OS)差有关,他汀类药物联合治疗在克服化疗耐药方面是有效的,特别是在ggpp高的SCLC中。然而,GGPS1在SCLC亚型中的表达模式及其与临床化疗反应的关系尚不清楚,GGPS1是否表明他汀类药物在化疗耐药SCLC中的敏感性有待进一步验证。通过对146例真实SCLC病例的综合分析,我们发现约25%的患者表现出GGPS1的高表达。亚组分析显示,GGPS1在ASCL1/NEUROD1/POU2F3三阴性亚组中表达较高。此外,GGPS1高表达与客观缓解率(ORR)、无进展生存期(PFS)和OS降低显著相关。此外,对7个配对活检样本的分析表明,GGPS1在化疗耐药SCLC中表达上调。我们进一步表明,依托泊苷和顺铂(E/P)联合他汀类药物在来自高GGPS1表达的复发患者的患者源异种移植(PDX)模型中具有改善的疗效。我们的研究结果表明,GGPS1是预测SCLC化疗耐药的有希望的生物标志物,可能是SCLC化疗耐药对他汀类药物联合治疗敏感性的潜在指标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
13.40
自引率
3.10%
发文量
460
审稿时长
2 months
期刊介绍: The International Journal of Cancer (IJC) is the official journal of the Union for International Cancer Control—UICC; it appears twice a month. IJC invites submission of manuscripts under a broad scope of topics relevant to experimental and clinical cancer research and publishes original Research Articles and Short Reports under the following categories: -Cancer Epidemiology- Cancer Genetics and Epigenetics- Infectious Causes of Cancer- Innovative Tools and Methods- Molecular Cancer Biology- Tumor Immunology and Microenvironment- Tumor Markers and Signatures- Cancer Therapy and Prevention
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