HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer.
HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer.
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DOI：
10.1371/journal.pbio.1000563
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发表时间：
2010-12-21
期刊：
影响因子：
9.8
通讯作者：
Kong A
中科院分区：
文献类型：
--
作者：
Gijsen M;King P;Perera T;Parker PJ;Harris AL;Larijani B;Kong A
HER2阳性乳腺癌患者在接受Herceptin治疗后，HER2受体信号传导和细胞存活维持在一个反馈回路中，但这种Herceptin耐药可能被泛her抑制剂绕过。赫赛汀（曲妥珠单抗）用于HER2 （ErbB2）阳性肿瘤的乳腺癌患者。然而，其作用机制和如何对赫赛汀产生获得性耐药仍然知之甚少。以前认为抗HER2单克隆抗体Herceptin抑制HER2信号传导，但最近的研究表明，Herceptin不降低HER2磷酸化。如果赫赛汀作为单药治疗，它不能消除HER2磷酸化可能是所有应答者不可避免地发生获得性耐药的关键原因。迄今为止，没有研究解释为什么赫赛汀不能消除HER2磷酸化。本研究的目的是研究为什么赫赛汀作为抗HER2单克隆抗体不能降低HER2磷酸化。我们还研究了急性和慢性赫赛汀治疗对her2阳性乳腺癌细胞中HER3和PKB磷酸化的影响。利用Förster共振能量转移（FRET）方法和传统的Western blot方法，我们发现了赫赛汀无法消除HER2磷酸化的分子机制。HER2磷酸化是通过配体介导的EGFR、HER3和HER4受体的激活来维持的，导致它们与HER2二聚化。HER配体的释放是由ADAM17通过PKB负反馈回路介导的。反馈回路被激活是因为赫赛汀治疗抑制PKB，因为当PKB抑制剂（Akt inhibitor VIII, Akti-1/2）抑制PKB磷酸化时，HER配体和ADAM17也会上调。赫赛汀与ADAM17抑制剂或panHER抑制剂JNJ-26483327联合使用能够消除反馈回路并降低HER2磷酸化。此外，赫赛汀联合JNJ-26483327在BT474异种移植瘤模型中具有协同抑制作用。我们已经确定，在赫赛汀治疗期间，PKB负反馈环连接ADAM17和HER配体，以维持HER2磷酸化。通过ADAM17激活其他HER受体可能介导her2过表达乳腺癌对Herceptin的获得性耐药。这一发现为克服这些患者的耐药性提供了治疗机会。我们建议赫赛汀应与panHER抑制剂或ADAM抑制剂联合使用，以克服her2阳性乳腺癌患者的获得性耐药。我们的结果也可能对其他靶向HER受体的治疗产生耐药性。HER2 （ErbB2）是一种表面蛋白，是表皮生长因子受体（EGFR）家族的成员，在大约五分之一的乳腺癌中过度表达。her2阳性的乳腺肿瘤往往具有很强的侵袭性，这种类型的肿瘤患者预后较差。一种名为曲妥珠单抗（赫赛汀）的治疗性单克隆抗体已被设计用于阻断HER2信号传导，并用于治疗HER2阳性乳腺癌患者。然而，最近的研究表明，赫赛汀不会降低HER2的活化。这可能就是为什么患者在接受赫赛汀单药治疗时总是产生耐药性的原因。迄今为止，还没有研究解释为什么赫赛汀作为一种抗HER2单克隆抗体不能消除HER2信号传导。我们发现，赫赛汀开启了一个反馈回路，增加了ADAM17蛋白的产生，ADAM17蛋白是一种蛋白酶，反过来又释放了激活HER （ErbB）受体的生长因子。这些生长因子激活HER2以及HER受体家族的其他成员egfr、HER3和her4，从而维持HER2阳性乳腺癌细胞中的HER2激活和细胞存活。我们发现，当Herceptin与ADAM17抑制剂联合使用时，细胞中的反馈回路被取消。此外，当与赫赛汀联合使用时，降低其他HER受体激活的泛HER抑制剂也可以抑制反馈回路并降低HER2激活。我们进一步证明，在乳腺癌动物模型中，赫赛汀与泛her抑制剂联合治疗比赫赛汀单独治疗更有效。我们相信我们的研究结果提供了治疗策略，可能有助于克服her2阳性乳腺癌患者获得性赫赛汀耐药。
A feedback loop maintains HER2 receptor signalling and cell survival in response to Herceptin treatment in HER2-positive breast cancers, but this Herceptin resistance may be bypassed by pan-HER inhibitors. Herceptin (trastuzumab) is used in patients with breast cancer who have HER2 (ErbB2)–positive tumours. However, its mechanisms of action and how acquired resistance to Herceptin occurs are still poorly understood. It was previously thought that the anti-HER2 monoclonal antibody Herceptin inhibits HER2 signalling, but recent studies have shown that Herceptin does not decrease HER2 phosphorylation. Its failure to abolish HER2 phosphorylation may be a key to why acquired resistance inevitably occurs for all responders if Herceptin is given as monotherapy. To date, no studies have explained why Herceptin does not abolish HER2 phosphorylation. The objective of this study was to investigate why Herceptin did not decrease HER2 phosphorylation despite being an anti-HER2 monoclonal antibody. We also investigated the effects of acute and chronic Herceptin treatment on HER3 and PKB phosphorylation in HER2-positive breast cancer cells. Using both Förster resonance energy transfer (FRET) methodology and conventional Western blot, we have found the molecular mechanisms whereby Herceptin fails to abolish HER2 phosphorylation. HER2 phosphorylation is maintained by ligand-mediated activation of EGFR, HER3, and HER4 receptors, resulting in their dimerisation with HER2. The release of HER ligands was mediated by ADAM17 through a PKB negative feedback loop. The feedback loop was activated because of the inhibition of PKB by Herceptin treatment since up-regulation of HER ligands and ADAM17 also occurred when PKB phosphorylation was inhibited by a PKB inhibitor (Akt inhibitor VIII, Akti-1/2). The combination of Herceptin with ADAM17 inhibitors or the panHER inhibitor JNJ-26483327 was able to abrogate the feedback loop and decrease HER2 phosphorylation. Furthermore, the combination of Herceptin with JNJ-26483327 was synergistic in tumour inhibition in a BT474 xenograft model. We have determined that a PKB negative feedback loop links ADAM17 and HER ligands in maintaining HER2 phosphorylation during Herceptin treatment. The activation of other HER receptors via ADAM17 may mediate acquired resistance to Herceptin in HER2-overexpressing breast cancer. This finding offers treatment opportunities for overcoming resistance in these patients. We propose that Herceptin should be combined with a panHER inhibitor or an ADAM inhibitor to overcome the acquired drug resistance for patients with HER2-positive breast cancer. Our results may also have implications for resistance to other therapies targeting HER receptors. HER2 (ErbB2) is a surface protein and member of the epidermal growth factor receptor (EGFR) family that is overexpressed in approximately one-fifth of breast cancers. HER2-positive breast tumours tend to be very aggressive, and patients with this type of tumour have a poor prognosis. A therapeutic monoclonal antibody called trastuzumab (Herceptin) has been designed to block HER2 signalling and is used as a treatment for patients with HER2-positive breast cancer. However, recent studies have shown that Herceptin does not decrease HER2 activation. This may be why patients invariably develop resistance if treated with Herceptin monotherapy. To date, no study has explained why Herceptin cannot abolish HER2 signalling despite being an anti-HER2 monoclonal antibody. We have found that Herceptin switches on a feedback loop that increases the production of the ADAM17 protein, a protease that in turn releases the growth factors that activate HER (ErbB) receptors. These growth factors activate HER2 and also the other members of the HER receptor family—EGFR, HER3 and HER4—in such a way as to maintain HER2 activation and cell survival in HER2-positive breast cancer cells. We have found that when Herceptin is provided in combination with ADAM17 inhibitors, the feedback loop is abrogated in cells. Furthermore, a pan-HER inhibitor that decreases the activation of other HER receptors can also inhibit the feedback loop and decrease HER2 activation when used in combination with Herceptin. We further demonstrated that the combination therapy of Herceptin with a pan-HER inhibitor is more effective than Herceptin alone in an animal model of breast cancer. We believe our results offer treatment strategies that may help overcome acquired Herceptin resistance in patients with HER2-positive breast cancer.
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影响因子：
3.7
作者：
Kong A;Calleja V;Leboucher P;Harris A;Parker PJ;Larijani B
通讯作者：
Larijani B
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
11.5
作者：
Magnifico, Alessandra;Albano, Luisa;Tagliabue, Elda
通讯作者：
Tagliabue, Elda
影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.