Liu Dongli, Glubb Dylan, O'Mara Tracy, Ford Caroline E
Gynaecological Cancer Research Group, Lowy Cancer Research Centre, School of Clinical Medicine, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, Australia.
Cancer Research Program, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Cancer Med. 2025 Jan;14(1):e70531. doi: 10.1002/cam4.70531.
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.
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.
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.
Together, these studies support further investigation of GZD824 as a potential therapeutic agent in endometrial cancer, potentially in combination with immune checkpoint inhibitors.
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重大挑战，尤其是对于该疾病的某些亚型。GZD824，也称为奥雷巴替尼，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抑制剂进行研究。本研究旨在探讨GZD824治疗子宫内膜癌的临床前疗效。
在此，我们对GZD824在七种子宫内膜癌细胞系（HEC-1-A、HEC-1-B、MFE296、RL95-2、Ishikawa、KLE和ARK-1）、一种源自正常永生化子宫内膜的细胞系（E6E7hTERT）以及从正常大网膜样本中分离的原代间皮细胞和成纤维细胞中进行了临床前评估。
GZD824抑制了所有子宫内膜癌细胞系的增殖，与正常细胞相比，这些细胞系对GZD824更为敏感（p = 0.030）。GZD824显著抑制Ishikawa（子宫内膜样）和ARK1（浆液性）子宫内膜癌细胞系的迁移，并显著抑制ARK1细胞的侵袭。通过RNA测序研究了在Ishikawa和ARK1细胞中两种剂量（0.1和1 μM）的GZD824后的全转录组调控，并在翻译水平研究了富集途径的关键成分。改变的关键途径包括ROR1/Wnt、GCN2-ATF4、上皮-间质转化（EMT）和PI3K-AKT。
总之，这些研究支持进一步研究GZD824作为子宫内膜癌的潜在治疗药物，可能与免疫检查点抑制剂联合使用。
