Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer. Rubicon has been established as a substrate of HUNK that is phosphorylated at serine (S) 92. Findings indicate that HUNK-mediated phosphorylation of Rubicon at S92 promotes both autophagy and tumorigenesis in HER2/neu+ breast cancer. HUNK inhibition prevents Rubicon S92 phosphorylation in HER2/neu+ breast cancer models and inhibits tumorigenesis. This study characterizes a downstream phosphorylation event as a measure of HUNK activity and identifies a selective HUNK inhibitor that has meaningful efficacy toward HER2+ breast cancer.

中文翻译：

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用于治疗 HER2+ 乳腺癌的有效选择性 HUNK 抑制剂的鉴定和表征

人表皮生长因子受体2（HER2）靶向药物已被证明是有效的，然而，对这些药物产生耐药性已成为治疗HER2+乳腺癌的障碍。有证据表明 HUNK 是原发性和耐药 HER2+ 乳腺癌的抗癌靶点。在这项研究中，HUNK 的选择性抑制剂与 HUNK 下游底物中的磷酸化事件一起被表征为 HER2+ 乳腺癌中 HUNK 活性的标志物。Rubicon 已被确定为 HUNK 的底物，其在丝氨酸 (S) 92 处被磷酸化。研究结果表明，HUNK 介导的 Rubicon 在 S92 处的磷酸化可促进 HER2/neu+ 乳腺癌中的自噬和肿瘤发生。HUNK 抑制可防止 HER2/neu+ 乳腺癌模型中的 Rubicon S92 磷酸化并抑制肿瘤发生。这项研究将下游磷酸化事件描述为 HUNK 活性的衡量标准，并确定了一种对 HER2+ 乳腺癌具有有意义疗效的选择性 HUNK 抑制剂。