The Multi-Kinase Inhibitor GZD824 (Olverembatinib) Shows Pre-Clinical Efficacy in Endometrial Cancer.

IF 2.9 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2025-01-01 DOI:10.1002/cam4.70531

Dongli Liu, Dylan Glubb, Tracy O'Mara, Caroline E Ford

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引用次数: 0

Abstract

Objective: Endometrial cancer is one of the few cancers for which mortality is still increasing. A lack of treatment options remains a major challenge, particularly for some subtypes of the disease. GZD824, also known as olverembatinib, is a multi-kinase inhibitor previously investigated in clinical trials for chronic myeloid leukaemia and Ph+ acute lymphoblastic leukaemia as a BCR-ABL inhibitor. This study aimed to investigate the pre-clinical efficacy of GZD824 for the treatment of EC.

Methods: Here, we undertook pre-clinical evaluation of GZD824 in seven endometrial cancer cell lines (HEC-1-A, HEC-1-B, MFE296, RL95-2, Ishikawa, KLE and ARK-1), one normal immortalised endometrium derived cell line (E6E7hTERT) and primary mesothelial and fibroblast cells isolated from normal omentum samples.

Results: GZD824 inhibited the proliferation of all endometrial cancer cell lines, which were significantly more sensitive to GZD824 compared to normal cells (p = 0.030). GZD824 significantly inhibited migration in Ishikawa (endometrioid) and ARK1 (serous) endometrial cancer cell lines and significantly inhibited invasion in the ARK1 cells. Whole transcriptome regulation following two doses (0.1 and 1 μM) of GZD824 in Ishikawa and ARK1 cells was investigated via RNA-seq, and key components of enriched pathways were investigated at the translational level. Key pathways altered included ROR1/Wnt, GCN2-ATF4, epithelial to mesenchymal transition (EMT) and PI3K-AKT.

Conclusion: Together, these studies support further investigation of GZD824 as a potential therapeutic agent in endometrial cancer, potentially in combination with immune checkpoint inhibitors.

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多激酶抑制剂GZD824 （Olverembatinib）在子宫内膜癌中的临床前疗效

目的：子宫内膜癌是少数死亡率仍在上升的癌症之一。缺乏治疗选择仍然是一个主要挑战，特别是对某些亚型的疾病。GZD824，也被称为olverembatinib，是一种多激酶抑制剂，先前在慢性髓性白血病和Ph+急性淋巴细胞白血病的临床试验中作为BCR-ABL抑制剂进行了研究。本研究旨在探讨GZD824治疗EC的临床前疗效。方法：我们在7种子宫内膜癌细胞系（HEC-1-A、HEC-1-B、MFE296、RL95-2、Ishikawa、KLE和ARK-1）、1种正常永生化子宫内膜来源细胞系（E6E7hTERT）和从正常大肠腺样本分离的原代间皮细胞和成纤维细胞中对GZD824进行了临床前评估。结果：GZD824对所有子宫内膜癌细胞的增殖均有抑制作用，与正常细胞相比，子宫内膜癌细胞对GZD824的敏感性显著提高（p = 0.030）。GZD824显著抑制石川（子宫内膜样）和ARK1（浆液性）子宫内膜癌细胞系的迁移，显著抑制ARK1细胞的侵袭。通过RNA-seq研究两种剂量（0.1 μM和1 μM） GZD824在Ishikawa和ARK1细胞中的全转录组调控，并在翻译水平上研究富集通路的关键组分。改变的关键通路包括ROR1/Wnt、GCN2-ATF4、上皮到间质转化（EMT）和PI3K-AKT。结论：这些研究支持进一步研究GZD824作为子宫内膜癌的潜在治疗剂，可能与免疫检查点抑制剂联合使用。

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

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.