Monoclonal antibody-induced ErbB3 receptor internalization and degradation inhibits growth and migration of human melanoma cells
Monoclonal antibody-induced ErbB3 receptor internalization and degradation inhibits growth and migration of human melanoma cells
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DOI：
10.4161/cc.19861
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发表时间：
2012-04-01
期刊：
影响因子：
4.3
通讯作者：
Ciliberto, Gennaro
中科院分区：
文献类型：
--
作者：
Belleudi, Francesca;Marra, Emanuele;Ciliberto, Gennaro
ErbB受体家族的成员是目前正在开发的用于治疗癌症的越来越多的小分子和单克隆抗体抑制剂的靶点。虽然历史上的努力一直针对ErbB 1（EGFR）和ErbB 2（HER 2/neu），新出现的证据指出ErbB 3作为激活ErbB受体家族增殖/存活途径的关键节点，并激发了对抗ErbB 3药物临床开发的热情。在这项研究中，我们评估了一组三个最近产生的抗人ErbB 3单克隆抗体，A2，A3和A4，在人原发性黑色素瘤细胞的潜在治疗效果。我们发现，在表达ErbB 1，ErbB 3和ErbB 4，但不是ErbB 2受体配体的黑色素瘤细胞激活PI 3 K/AKT通路，这导致增加细胞增殖和迁移。虽然抗体A3和A4能够有效地抑制配体诱导的信号传导、增殖和迁移，但抗体A2不能发挥这种作用。为了试图理解这种不同行为的作用机制和基础，我们通过一系列组合方法证明，抗体功效与抗体诱导的受体内化、降解和抑制受体再循环至细胞表面密切相关。最后，通过肽阵列的精细表位作图研究表明，抑制性抗体与非抑制性抗体具有与受体胞外结构域显著不同的结合模式。我们的研究证实了ErbB 3的关键作用，并指出开发新的联合疗法治疗恶性黑色素瘤。
Members of the ErbB receptor family are targets of a growing numbers of small molecules and monoclonal antibodies inhibitors currently under development for the treatment of cancer. Although historical efforts have been directed against ErbB1 (EGFR) and ErbB2 (HER2/neu), emerging evidences have pointed to ErbB3 as a key node in the activation of proliferation/survival pathways from the ErbB receptor family and have fueled enthusiasm toward the clinical development of anti-ErbB3 agents. In this study, we have evaluated the potential therapeutic efficacy of a set of three recently generated anti-human ErbB3 monoclonals, A2, A3 and A4, in human primary melanoma cells. We show that in melanoma cells expressing ErbB1, ErbB3 and ErbB4 but not ErbB2 receptor ligands activate the PI3K/AKT pathway, and this leads to increased cell proliferation and migration. While antibodies A3 and A4 are able to potently inhibit ligand-induced signaling, proliferation and migration, antibody A2 is unable to exert this effect. In attempt to understand the mechanism of action and the basis of this different behavior, we demonstrate, through a series of combined approaches, that antibody efficacy strongly correlates with antibody-induced receptor internalization, degradation and inhibition of receptor recycling to the cell surface. Finally, fine epitope mapping studies through a peptide array show that inhibiting vs. non-inhibiting antibodies have a dramatically different mode of binding to the receptor extracellular domain. Our study confirms the key role of ErbB3 and points to exploitation of novel combination therapies for treatment of malignant melanoma.