Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells
Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells
复制标题
DOI：
10.1158/0008-5472.can-04-3841
复制
发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Esteva, FJ
中科院分区：
文献类型：
--
作者：
Nahta, R;Yuan, LYH;Esteva, FJ
大多数对人表皮生长因子受体2（HER-2）靶向抗体曲妥珠单抗达到初始治疗反应的乳腺癌患者将在1年内显示疾病进展。我们先前报道了SKBR 3衍生的曲妥珠单抗耐药池的表征。在目前的研究中，我们发现HER-2与胰岛素样生长因子-I受体（IGF-IR）的相互作用在这些耐药细胞中是独一无二的，而在亲本曲妥珠单抗敏感细胞中则不然。IGF-I刺激导致耐药细胞中HER-2磷酸化增加，而不是亲代细胞中HER-2磷酸化增加，以及IGF-IR酪氨酸激酶活性抑制导致HER-2磷酸化减少，证明IGF-IR和RER-2之间的串扰仅在耐药细胞中发生。仅在耐药细胞中。此外，I-OMe-AG 538抑制IGF-IR酪氨酸激酶活性增加了耐药细胞对曲妥珠单抗的敏感性。HER-2/IGF-IR相互作用在抗性细胞暴露于抗14317-IR抗体α-1113时被破坏，并且在较小程度上，当暴露于抗HER-2抗体帕妥珠单抗时被破坏。通过α-1113的异二聚体破坏显著恢复了对曲妥珠单抗的敏感性，并且耐药细胞显示相对于亲本细胞对帕妥珠单抗的敏感性略微增加。α-IR 3和帕妥珠单抗均未降低HER-2磷酸化，表明当HER-2和IGF-IR不物理结合时，存在除IGF-IR以外的其他磷酸化来源。我们的数据支持在曲妥珠单抗耐药细胞中HER-2和IGF-IR之间的独特相互作用，使得IGF-IR和HER-2之间发生串扰。这些数据表明，IGF-IR/HER-2异二聚体有助于曲妥珠单抗耐药，并证明需要进一步研究，检查这种复合物作为在曲妥珠单抗治疗期间进展的乳腺癌的潜在治疗靶点。
The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within I year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and RER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti-14317-IR antibody alpha-1113 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by alpha-1113 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither alpha-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.