Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells
Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells
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DOI：
10.4161/15384101.2014.994966
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发表时间：
2015-02-15
期刊：
影响因子：
4.3
通讯作者：
Kurokawa, Manabu
中科院分区：
文献类型：
--
作者：
Canfield, Kaleigh;Li, Jiaqi;Kurokawa, Manabu
大约25%的乳腺癌过度表达并依赖于受体酪氨酸激酶ERBB2，ERBB家族的4个成员之一。针对ERBB2的靶向治疗已被开发并应用于临床，但许多患者仍对此类治疗产生抵抗力。尽管很多工作都集中在阐明ERBB2靶向治疗获得性耐药的机制上，但ERBB4的参与仍然难以捉摸，也存在争议。我们证明，基因消融ERBB4，而不是ErbB1-3，导致了拉帕替尼耐药细胞的凋亡，这表明PAN-ERBB抑制剂的疗效至少部分是通过抑制ERBB4介导的。此外，ERBB4在体外被选为对拉帕替尼具有获得性耐药的乳腺癌细胞系中，以及在长期治疗拉帕替尼的MMTV-Neu小鼠中，在蛋白质水平上被上调。ERBB4基因敲除导致耐药细胞中AKT磷酸化水平下降，但在敏感细胞中无此作用，提示ERBB4激活了拉帕替尼耐药细胞中的PI3K/AKT通路。重要的是，ERBB4基因敲除不仅引发了对雷帕替尼耐药的细胞的凋亡，也引发了对曲妥珠单抗耐药的细胞的凋亡。我们的结果表明，虽然ERBB4对于ERBB2+乳腺癌细胞来说是必不可少的，但在ERBB2+癌细胞对ERBB2抑制剂、拉帕替尼和曲妥珠单抗产生耐药性后，ERBB4可能在ERBB2+癌细胞的生存中发挥关键作用。
Approximately 25% of breast cancers overexpress and depend on the receptor tyrosine kinase ERBB2, one of 4 ERBB family members. Targeted therapies directed against ERBB2 have been developed and used clinically, but many patients continue to develop resistance to such therapies. Although much effort has been focused on elucidating the mechanisms of acquired resistance to ERBB2-targeted therapies, the involvement of ERBB4 remains elusive and controversial. We demonstrate that genetic ablation of ERBB4, but not ERBB1-3, led to apoptosis in lapatinib-resistant cells, suggesting that the efficacy of pan-ERBB inhibitors was, at least in part, mediated by the inhibition of ERBB4. Moreover, ERBB4 was upregulated at the protein level in ERBB2+ breast cancer cell lines selected for acquired lapatinib resistance in vitro and in MMTV-Neu mice following prolonged lapatinib treatment. Knockdown of ERBB4 caused a decrease in AKT phosphorylation in resistant cells but not in sensitive cells, suggesting that ERBB4 activated the PI3K/AKT pathway in lapatinib-resistant cells. Importantly, ERBB4 knockdown triggered apoptosis not only in lapatinib-resistant cells but also in trastuzumab-resistant cells. Our results suggest that although ERBB4 is dispensable for naive ERBB2+ breast cancer cells, it may play a key role in the survival of ERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors, lapatinib and trastuzumab.