Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China.
Department of Laboratory Medicine, Peking University Third Hospital, Beijing, 100191, China.
Gastric Cancer. 2024 Jul;27(4):785-801. doi: 10.1007/s10120-024-01508-3. Epub 2024 May 23.
Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a heterogeneous GC subtype characterized by the overexpression of HER2. To date, few specific targeted therapies have demonstrated durable efficacy in HER2-positive GC patients, with resistance to trastuzumab typically emerging within 1 year. However, the mechanisms of resistance to trastuzumab remain incompletely understood, presenting a significant challenge to clinical practice.
In this study, we integrated genetic screening and bulk transcriptome and epigenomic profiling to define the mechanisms mediating adaptive resistance to HER2 inhibitors and identify potential effective therapeutic strategies for treating HER2-positive GCs.
We revealed a potential association between adaptive resistance to trastuzumab in HER2-positive GC and the expression of YES-associated protein (YAP). Notably, our investigation revealed that long-term administration of trastuzumab triggers extensive chromatin remodeling and initiates YAP gene transcription in HER2-positive cells characterized by the initial inhibition and subsequent reactivation. Furthermore, treatment of HER2-positive GC cells and cell line-derived xenografts (CDX) models with YAP inhibitors in combination with trastuzumab was found to induce synergistic effects through the AKT/mTOR and ERK/mTOR pathways.
These findings underscore the pivotal role of reactivated YAP and mTOR signaling pathways in the development of adaptive resistance to trastuzumab and may serve as a promising joint target to overcome resistance to trastuzumab.
人表皮生长因子受体 2（HER2）阳性胃癌（GC）是一种异质性 GC 亚型，其特征是 HER2 过表达。迄今为止，很少有特定的靶向治疗在 HER2 阳性 GC 患者中显示出持久的疗效，曲妥珠单抗的耐药性通常在 1 年内出现。然而，曲妥珠单抗耐药的机制仍不完全清楚，这给临床实践带来了重大挑战。
在这项研究中，我们整合了遗传筛选和批量转录组和表观基因组谱，以定义介导 HER2 抑制剂适应性耐药的机制，并确定治疗 HER2 阳性 GCs 的潜在有效治疗策略。
我们揭示了 HER2 阳性 GC 中曲妥珠单抗适应性耐药与 YES 相关蛋白（YAP）的表达之间的潜在关联。值得注意的是，我们的研究表明，曲妥珠单抗的长期给药会触发广泛的染色质重塑，并在最初抑制随后再激活的 HER2 阳性细胞中启动 YAP 基因转录。此外，在 HER2 阳性 GC 细胞和细胞系衍生的异种移植（CDX）模型中，YAP 抑制剂与曲妥珠单抗联合使用被发现通过 AKT/mTOR 和 ERK/mTOR 途径诱导协同效应。
这些发现强调了再激活的 YAP 和 mTOR 信号通路在曲妥珠单抗适应性耐药发展中的关键作用，并可能成为克服曲妥珠单抗耐药的有前途的联合靶标。
