PO.ET02.14 · 实验与分子治疗
双重靶向GLI1和EZH2治疗侵袭性乳腺癌
Dual targeting GLI1 and EZH2 for treatment of invasive breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
约12%的乳腺癌为侵袭性乳腺癌，包括三阴性乳腺癌（TNBC），其表现为早期转移和复发，治疗选择有限。因此，迫切需要更好地理解调控侵袭性乳腺癌的关键机制，以开发有效的治疗策略。我们的临床数据库分析表明，EZH2过表达常与转移性乳腺癌相关，而致癌性GLI1-Hedgehog信号的高表达与侵袭性乳腺癌的不良生存呈正相关。我们的初步研究结果表明，EZH2基因缺失会导致GLI1及其下游靶基因cyclin D1的表达水平降低。既往文献也提示，cMYC可激活GLI1，而EZH2-cMYC复合物能够以非典型方式诱导靶基因表达，从而促进癌症。然而，据报道，单独临床使用EZH2抑制剂或单独使用GLI1抑制剂均无法阻碍肿瘤生长或转移。我们的数据提示EZH2可能调控GLI1表达，但其协同功能尚未完全阐明。我们预期EZH2与cMYC和GLI1形成复合物，协同激活参与乳腺癌进展的靶基因（例如GLI1和Cyclin D1）。因此，EZH2抑制剂与GLI1抑制剂的联合使用能够协同抑制癌细胞生长和转移，可作为侵袭性乳腺癌一种新的有效治疗选择。通过细胞活力测定发现，与单药治疗和溶媒对照组相比，联合治疗在抑制TNBC细胞活力方面更为有效。划痕愈合实验表明，联合治疗在抑制TNBC细胞迁移方面更为有效。采用CompuSyn进行的药物协同分析显示，联合指数（CI）和剂量减少指数（DRI）均表明联合治疗表现出显著的协同效应，其中Vismodegib可将剂量减少约52倍，而GSK126可将剂量减少约22倍。基于这些发现，我们认为双重靶向GLI1-EZH2有潜力成为临床上针对侵袭性乳腺癌的一种新型有效联合治疗方案。
查看英文原文 English abstract
About 12% of breast cancers are invasive breast cancers, including triple-negative breast cancer (TNBC), which manifests early metastasis and recurrence with limited treatment options. Therefore, there is an urgent need to better understand key mechanisms governing invasive breast cancers to develop effective treatment strategies. Our clinical database analysis indicates that overexpression of EZH2 is often correlated with metastatic breast cancer, and high expression of the oncogenic GLI1-Hedgehog signaling is positively correlated with poor survival of invasive breast cancers. Our pilot findings indicate that deletion of the EZH2 gene results in reduced expression levels of GLI1 and its downstream target gene, cyclin D1. Previous literature also suggests that cMYC can activate GLI1, and the EZH2-cMYC complex can induce target gene expression in an atypical manner, promoting cancer. However, it is reported that the clinical use of either an EZH2 inhibitor alone or a GLI1 inhibitor alone cannot hinder tumor growth or metastasis. Our data suggest that EZH2 may regulate GLI1 expression, but its synergistic functionality has not been fully elucidated. We expect that EZH2 forms a complex with cMYC and GLI1 to synergistically activate the target genes involved in breast cancer progression (for example, GLI1 and Cyclin D1). As a result, a combination of EZH2 inhibitors and GLI1 inhibitors can synergistically suppress cancer cell growth and metastasis, serving as a new and effective therapeutic option for invasive breast cancers. Using a cell viability assay, the combination therapy was shown to be more effective in inhibiting TNBC cell viability compared to the single-drug treatment and the vehicle groups. The wound healing assay showed that combination therapy was more effective in suppressing TNBC cell migration. The CompuSyn for drug synergy analysis, both the Combination Index (CI) and Dose Reduction Index (DRI) indicated that the combination therapy exhibited significant synergistic effects, where Vismodegib could reduce the dose by ~52-fold, while GSK126 could reduce the dose by ~22-fold. Form the findings, we believe that dual targeting GLI1-EZH2 has potential to become a novel and effective combination treatment for invasive breast cancer in the clinical setting.
利益披露 Disclosure
J. Yang, None..
C. Chang, None..
Y. Lai, None.