Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non-responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways.

中文翻译：

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依鲁替尼对ERBB4的抑制作用以WNT5A依赖性方式降低细胞生长。

ERBB家族成员的改变与许多肿瘤恶性肿瘤有关。EGFR和ERBB2已在临床肿瘤学中进行了广泛研究，目前有几种药物将其靶向治疗。然而，尽管ERBB4在许多实体瘤中过表达或突变，但ERBB4作为潜在治疗靶标的意义仍未得到充分探讨。使用独特的功能性蛋白质微阵列平台，我们发现依鲁替尼在与其规范靶标BTK相同的nM范围内抑制ERBB4活性。基于细胞的分析显示，在具有高水平内源性ERBB4的癌细胞系中，依鲁替尼治疗抑制细胞生长并降低ERBB4和下游靶标MEK和ERK的磷酸化。在体内，对依鲁替尼有反应的小鼠异种移植肿瘤在经依鲁替尼治疗后显示出减小的肿瘤体积。有趣的是，响应性和非响应性细胞之间的全球基因表达比较确定了一个特征在于WNT信号的特征，该信号可预测对依鲁替尼的生长响应性。无应答的ERBB4表达细胞系通过WNT5A的过表达，提高了WNT途径的活性。此外，WNT5A表达的抑制导致非反应性细胞系中的依鲁替尼反应。我们的数据表明，抑制ERBB4会降低具有低WNT5A表达的细胞的细胞生长，并揭示ERBB4与WNT途径之间的联系。此外，WNT5A表达的抑制导致非反应性细胞系中的依鲁替尼反应。我们的数据表明，抑制ERBB4会降低具有低WNT5A表达的细胞的细胞生长，并揭示ERBB4与WNT途径之间的联系。此外，WNT5A表达的抑制导致非反应性细胞系中的依鲁替尼反应。我们的数据表明，抑制ERBB4会降低具有低WNT5A表达的细胞的细胞生长，并揭示ERBB4与WNT途径之间的联系。