ErbB2 overexpression identifies a subclass of breast cancer as ErbB2-positive that is frequently associated with poor prognosis. Current ErbB2-targeted therapies have profoundly improved patient outcomes, but mutations occurring in ErbB2 have been shown to confer drug resistance. Induction of ErbB2 degradation was proposed as an intriguing strategy to battle with ErbB2-positive breast cancer and reduced mutation-incurred drug resistance. Although multiple HSP90 inhibitors have been demonstrated to effectively trigger ErbB2 degradation, none succeeded in the clinical evaluations. To develop novel ErbB2-targeting strategies, we investigated the endocytic degradation and reversible ubiquitylation of ErbB2 in breast cancer. In this study, we reveal that HSP90 inhibition leads to efficient ubiquitylation and endocytic degradation of ErbB2 through the canonical endo-lysosomal route. USP2 associates with internalized ErbB2 and prevents its lysosomal sorting and degradation via exerting deubiquitylase activity. Accordingly, the USP2 inhibitor ML364 is capable of inducing ErbB2 ubiquitylation and accelerating its turnover. ML364 potentiates the pro-degradation effects of HSP90 inhibitors on ErbB2 and hence sensitizes ErbB2-positive breast cancer cells to HSP90 inhibition. The combination of USP2 and HSP90 inhibitors effectively restrains ErbB2-positive breast cancer xenograft growth in vivo. Based on these observations, we conclude that USP2 safeguards ErbB2 surface levels by antagonizing its ubiquitylation-mediated endocytic degradation, which can be exploited to design novel therapeutic strategies against ErbB2-driven malignancies as combinatorial treatment with HSP90 inhibitors.

中文翻译：

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去泛素化酶 USP2 通过抵抗内吞降解来维持 ErbB2 的丰度，并代表 ErbB2 阳性乳腺癌的治疗靶点。

ErbB2 过表达将乳腺癌的一个亚类鉴定为 ErbB2 阳性，这通常与不良预后相关。目前的 ErbB2 靶向疗法已经极大地改善了患者的治疗效果，但 ErbB2 中发生的突变已被证明会产生耐药性。诱导 ErbB2 降解被提议作为对抗 ErbB2 阳性乳腺癌和减少突变引起的耐药性的一种有趣策略。尽管已证明多种 HSP90 抑制剂可有效触发 ErbB2 降解，但没有一个在临床评估中取得成功。为了开发新的 ErbB2 靶向策略，我们研究了 ErbB2 在乳腺癌中的内吞降解和可逆泛素化。在这项研究中，我们揭示了 HSP90 抑制通过典型的内溶酶体途径导致 ErbB2 的有效泛素化和内吞降解。USP2 与内化的 ErbB2 相关联，并通过发挥去泛素化酶活性阻止其溶酶体分类和降解。因此，USP2 抑制剂 ML364 能够诱导 ErbB2 泛素化并加速其周转。ML364 增强 HSP90 抑制剂对 ErbB2 的促降解作用，从而使 ErbB2 阳性乳腺癌细胞对 HSP90 抑制敏感。USP2 和 HSP90 抑制剂的组合有效地抑制了 ErbB2 阳性乳腺癌异种移植物的体内生长。基于这些观察，我们得出结论，USP2 通过拮抗其泛素化介导的内吞降解来保护 ErbB2 表面水平，