Background

To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance.

Methods

In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773).

Results

Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro.

Conclusion

Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.

中文翻译：

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WEE1 抑制可逆转 HER2 阳性癌症中的曲妥珠单抗耐药性

背景

迄今为止，已经做出了许多努力来了解曲妥珠单抗在人表皮生长因子受体 2 (HER2) 阳性乳腺癌和胃癌中的耐药机制。然而，对曲妥珠单抗耐药的患者仍有巨大的医疗需求未得到满足。

方法

在我们的研究中，我们从ERBB2扩增的胃癌和胆道癌细胞系（SNU-216、NCI-N87、SNU-2670 和 SNU-2773）中产生了四种抗曲妥珠单抗 (HR) 癌细胞系。

结果

在这里，我们发现曲妥珠单抗耐药 (HR) HER2 阳性癌细胞中的 PD-L1 表达高于亲代细胞，并且阻断 PD-L1 逆转了 HR 细胞对曲妥珠单抗的耐药性。曲妥珠单抗通过 NF-κB 激活在亲代和 HR 细胞中上调 PD-L1 表达，然而，仅在亲代细胞中导致 DNA 损伤。下调 PD-L1 表达的 WEE1 抑制剂 adavosertib 通过阻断 BRCA1-CMTM6-PD-L1 信号和 HER2-CDCP-1-SRC 轴增强了曲妥珠单抗的疗效。此外，在体外存在人 PBMC 的情况下，通过阻断 WEE1 可降低 galectin-9、CD163、FoxP3 和 CTLA-4 的水平。

结论

总之，共同靶向 HER2 和 WEE1 的策略可以克服 HER2 阳性癌症对曲妥珠单抗的耐药性，支持 HER2 阳性癌症患者的进一步临床开发。