Department of Pathology, First Affiliated Hospital, Gannan Medical University, Ganzhou, 341000, China.
Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, 1 Hexie Road, Rongjiang New District, Ganzhou, 341000, China.
J Exp Clin Cancer Res. 2024 Feb 26;43(1):56. doi: 10.1186/s13046-024-02981-5.
Ovarian cancer (OC) is a prevalent malignancy in the female reproductive system, and developing effective targeted therapies for this disease remains challenging. The aim of this study was to use clinically-relevant OC models to evaluate the therapeutic effectiveness of RC48, an antibody-drug conjugate (ADC) targeting HER2, either alone or in combination with the VEGFR inhibitor Cediranib Maleate (CM), for the treatment of advanced OC.
OC tumor specimens and cell lines were analyzed to determine HER2 and VEGFR expression by Western blot, immunocytochemistry and immunofluorescence. Moreover, the OC cell lines, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were treated with RC48 and/or CM and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for OC both in vitro and in vivo. Additionally, RNA-Seq was performed to investigate the critical mechanism underlying the combination therapy of RC48 and CM.
Our results demonstrated that RC48 alone effectively targeted and inhibited the growth of HER2-positive OC tumors in both cell lines and PDX models. Furthermore, the combination of RC48 and CM synergistically induced tumor regression in human OC cell lines, as well as CDX and PDX models. Mechanistically, we observed that the combination treatment inhibited the growth of OC cells involved inducing apoptosis and suppressing cell motility. RNA-seq analysis provided further mechanistic insights and revealed that co-administration of RC48 and CM downregulated multiple cancer-related pathways, including the AKT/mTOR pathway, cell cycle, and cell proliferation. Notably, our data further confirmed that the PI3K-AKT pathway played a key role in the inhibition of proliferation triggered by combinational treatment of RC48 and CM in OC cells.
These findings provide a preclinical framework supporting the potential of dual targeting HER2 and VEGFR as a promising therapeutic strategy to improve outcomes in patients with OC.
卵巢癌（OC）是女性生殖系统中常见的恶性肿瘤，开发针对这种疾病的有效靶向治疗仍然具有挑战性。本研究旨在使用临床相关的 OC 模型来评估 RC48（一种针对 HER2 的抗体药物偶联物（ADC））单独或联合 VEGFR 抑制剂 Cediranib Maleate（CM）治疗晚期 OC 的治疗效果。
通过 Western blot、免疫细胞化学和免疫荧光分析 OC 肿瘤标本和细胞系中 HER2 和 VEGFR 的表达。此外，还对 OC 细胞系、细胞衍生的异种移植（CDX）和患者衍生的异种移植（PDX）模型进行了 RC48 和/或 CM 治疗，然后进行细胞增殖、活力、凋亡和肿瘤生长分析，以评估 RC48 和 CM 联合治疗 OC 的可行性在体外和体内。此外，进行了 RNA-Seq 分析，以研究 RC48 和 CM 联合治疗的关键机制。
我们的结果表明，RC48 单独有效地靶向和抑制了 HER2 阳性 OC 肿瘤在细胞系和 PDX 模型中的生长。此外，RC48 和 CM 的联合治疗协同诱导了人 OC 细胞系以及 CDX 和 PDX 模型中的肿瘤消退。在机制上，我们观察到联合治疗通过诱导细胞凋亡和抑制细胞迁移来抑制 OC 细胞的生长。RNA-seq 分析提供了进一步的机制见解，并揭示了联合治疗下调了多个与癌症相关的途径，包括 AKT/mTOR 途径、细胞周期和细胞增殖。值得注意的是，我们的数据进一步证实了 PI3K-AKT 途径在 OC 细胞中联合治疗 RC48 和 CM 触发的增殖抑制中起关键作用。
这些发现为双重靶向 HER2 和 VEGFR 作为改善 OC 患者结局的有前途的治疗策略提供了临床前框架。
