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 过度表达。迄今为止，很少有特定的靶向治疗能够在 HER2 阳性 GC 患者中表现出持久疗效，曲妥珠单抗通常在 1 年内出现耐药性。然而，曲妥珠单抗的耐药机制仍不完全清楚，这对临床实践提出了重大挑战。在这项研究中，我们整合了基因筛查、大量转录组和表观基因组分析，以明确介导 HER2 抑制剂适应性耐药的机制，并确定潜在的有效治疗策略用于治疗 HER2 阳性 GC。我们揭示了 HER2 阳性 GC 对曲妥珠单抗的适应性耐药与 YES 相关蛋白 (YAP) 表达之间的潜在关联。值得注意的是，我们的研究表明，长期给予曲妥珠单抗会引发广泛的染色质重塑，并在 HER2 阳性细胞中启动 YAP 基因转录，其特征是最初的抑制和随后的重新激活。此外，发现用 YAP 抑制剂与曲妥珠单抗联合治疗 HER2 阳性 GC 细胞和细胞系来源的异种移植物 (CDX) 模型，可通过 AKT/mTOR 和 ERK/mTOR 途径产生协同效应。这些发现强调了在曲妥珠单抗适应性耐药的发展中重新激活 YAP 和 mTOR 信号通路，并可能作为克服曲妥珠单抗耐药性的有希望的联合靶标。© 2024。作者。

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.© 2024. The Author(s).