Human epidermal growth factor receptor 2 (HER2) is an oncogenic receptor tyrosine kinase amplified in approximately 20% of breast cancer (BC). HER2-targeted therapies are the linchpin of treating HER2-positive BC. However, drug resistance is common, and the main resistance mechanism is unknown. We tested the hypothesis that drug resistance results mainly from inadequate or lack of inhibition of HER2 and its family member epidermal growth factor receptor (EGFR). We used clinically relevant cell and tumor models to assess the impact of targeted degradation of HER2 and EGFR on trastuzumab resistance. Trastuzumab is the most common clinically used HER2 inhibitor. Targeted degradation of HER2 and EGFR was achieved using recombinant human protein PEPD, which binds to the extracellular domains of the receptors. siRNA knockdown was used to assess the relative importance of EGFR and HER2 in trastuzumab resistance. Both HER2 and EGFR are overexpressed in all trastuzumab-resistant HER2-positive BC cell and tumor models and that all trastuzumab-resistant models are highly vulnerable to targeted degradation of HER2 and EGFR. Degradation of HER2 and EGFR induced by PEPD causes extensive inhibition of oncogenic signaling in trastuzumab-resistant HER2-positive BC cells. This is accompanied by strong growth inhibition of cultured cells, orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of trastuzumab-resistant HER2-positive BC. siRNA knockdown indicates that eliminating both HER2 and EGFR is necessary to maximize therapeutic outcome. This study unravels the therapeutic vulnerability of trastuzumab-resistant HER2-positive BC and shows that an agent that targets the degradation of both HER2 and EGFR is highly effective in overcoming drug resistance in this disease. The findings provide new insights and innovations for advancing treatment of drug-resistant HER2-positive breast cancer that remains an unmet problem.

中文翻译：

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HER2 和 EGFR 的靶向双重降解消除了致癌信号，克服了治疗耐药性，并抑制了 HER2 阳性乳腺癌模型中的转移性病变

人表皮生长因子受体 2 (HER2) 是一种致癌受体酪氨酸激酶，在大约 20% 的乳腺癌 (BC) 中扩增。 HER2 靶向治疗是治疗 HER2 阳性 BC 的关键。但耐药现象普遍存在，且主要耐药机制尚不清楚。我们检验了这样的假设：耐药性主要是由于 HER2 及其家族成员表皮生长因子受体 (EGFR) 抑制不足或缺乏造成的。我们使用临床相关细胞和肿瘤模型来评估 HER2 和 EGFR 靶向降解对曲妥珠单抗耐药性的影响。曲妥珠单抗是临床上最常用的 HER2 抑制剂。使用重组人蛋白 PEPD 实现 HER2 和 EGFR 的靶向降解，该蛋白与受体的胞外结构域结合。 siRNA 敲低用于评估 EGFR 和 HER2 在曲妥珠单抗耐药性中的相对重要性。 HER2 和 EGFR 在所有曲妥珠单抗耐药 HER2 阳性 BC 细胞和肿瘤模型中均过表达，并且所有曲妥珠单抗耐药模型都极易受到 HER2 和 EGFR 的靶向降解。 PEPD 诱导的 HER2 和 EGFR 降解导致曲妥珠单抗耐药 HER2 阳性 BC 细胞中致癌信号传导的广泛抑制。伴随着培养细胞、原位患者来源的异种移植物以及曲妥珠单抗耐药 HER2 阳性 BC 脑和肺转移灶的强烈生长抑制。 siRNA 敲低表明消除 HER2 和 EGFR 对于最大限度地提高治疗效果是必要的。这项研究揭示了曲妥珠单抗耐药 HER2 阳性 BC 的治疗脆弱性，并表明针对 HER2 和 EGFR 降解的药物在克服该疾病的耐药性方面非常有效。这些发现为推进耐药 HER2 阳性乳腺癌的治疗提供了新的见解和创新，这一问题仍然是一个未解决的问题。