背景:人表皮生长因子受体2(HER2)阳性胃癌(GC)是一种异质GC亚型,其特征是HER2的过表达。迄今为止,很少有特定的靶向治疗在HER2阳性GC患者中表现出持久的疗效,对曲妥珠单抗的耐药性通常在1年内出现。然而,对曲妥珠单抗的耐药机制仍未完全了解,对临床实践提出了重大挑战。
方法:在本研究中,我们整合了遗传筛查和整体转录组和表观基因组分析,以确定介导HER2抑制剂适应性耐药的机制,并确定治疗HER2阳性GC的潜在有效治疗策略.
结果: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,我们的调查显示,长期服用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再激活.此外,发现用YAP抑制剂联合曲妥珠单抗治疗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途径诱导协同作用.
结论:这些发现强调了重新激活的YAP和mTOR信号通路在曲妥珠单抗适应性耐药性发展中的关键作用,并且可能作为克服曲妥珠单抗耐药性的一个有希望的联合靶点。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.