Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.

中文翻译：

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DUSP6 抑制克服了 HER2+ 乳腺癌中神经调节蛋白/HER3 驱动的治疗耐受性。


尽管酪氨酸激酶抑制剂 （TKI） 在癌症中具有临床益处，但大多数肿瘤可以在 TKI 治疗下重新激活增殖。在这里，我们展示了 HER2 + 乳腺癌细胞在连续 HER2 抑制剂 （HER2i） 治疗下从休眠药物耐受细胞转变为再增殖细胞的转录谱。专注于磷酸酶，发现双特异性磷酸酶 DUSP6 的表达在休眠细胞中受到抑制，但在再生时强烈诱导。DUSP6 表达也选择性地与 HER2+ 乳腺癌患者的不良生存率相关。DUSP6 过表达赋予细胞凋亡耐药性，而其药理学阻断阻止了 HER2i 治疗下的治疗耐受性发展。DUSP6 靶向也与临床使用的 HER2i 联合疗法协同作用。从机制上讲，DUSP6 是 HER3 表达的正调节因子，其对 HER2i 耐受性的影响是由神经调节蛋白-HER3 轴介导的。在体内，DUSP6 的遗传靶向减少了脑转移模型中的肿瘤生长，而其药理学靶向与 HER2i 联合诱导合成致死治疗效果。总的来说，这项工作表明 DUSP6 驱动逃脱了 HER2i 诱导的休眠，并且 DUSP6 是克服 HER3 驱动的 TKI 耐药的可成药靶点。