Combination therapy with anti-ErbB3 monoclonal antibodies and EGFR TKIs potently inhibits Non-small Cell Lung Cancer
Combination therapy with anti-ErbB3 monoclonal antibodies and EGFR TKIs potently inhibits Non-small Cell Lung Cancer
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DOI：
10.18632/oncotarget.1141
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发表时间：
2013-08-01
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影响因子：
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通讯作者：
Ciliberto, Gennaro
中科院分区：
文献类型：
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作者：
Noto, Alessia;De Vitis, Claudia;Ciliberto, Gennaro
晚期非小细胞肺癌（NSCLC）的个性化治疗已通过引入EGFR酪氨酸激酶抑制剂（TKI）、吉非替尼和厄洛替尼而得到改善。EGFR TKI可诱导显著的客观缓解，并增加EGFR胞浆内酪氨酸激酶结构域发生致敏突变的患者的生存期。然而，几乎所有患者都会产生耐药性，这是疾病复发的原因。因此，正在进行一些努力来了解耐药机制，以开发能够使耐药细胞对EGFR TKI敏感的联合治疗。最近的研究表明，EGFR受体家族的另一个成员，即ErbB 3的上调通过其胞质内结构域的磷酸化增加和PI 3 K/AKT信号转导的激活参与耐药性。在本文中，我们首先通过使用一组来自肺腺癌患者的恶性胸腔积液衍生细胞培养物（MPEDCC）表明，表面ErbB 3表达与AKT磷酸化增加相关。针对ErbB 3的抗体，即A3，我们先前证明其仅在过表达表面ErbB 3的细胞中诱导受体内化和降解、抑制生长并诱导凋亡。此外，抗ErbB 3抗体与EGFR TKI的组合在体外协同影响细胞增殖，引起细胞周期停滞，上调p21表达并抑制小鼠异种移植物中的肿瘤生长。重要的是，抗ErbB 3抗体对吉非替尼的增强作用发生在从头和从头耐药细胞中。抗ErbB 3 mAb还与EGFR和HER 2双重抑制剂拉帕替尼具有强烈协同作用。我们的研究结果表明，EGFR TKI和抗ErbB 3抗体的联合治疗应该是一种有前途的方法，在临床上追求。
Personalized therapy of advanced non-small cell lung cancer (NSCLC) has been improved by the introduction of EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. EGFR TKIs induce dramatic objective responses and increase survival in patients bearing sensitizing mutations in the EGFR intracytoplasmic tyrosine kinase domain. However, virtually all patients develop resistance, and this is responsible for disease relapse. Hence several efforts are being undertaken to understand the mechanisms of resistance in order to develop combination treatments capable to sensitize resistant cells to EGFR TKIs. Recent studies have suggested that upregulation of another member of the EGFR receptor family, namely ErbB3 is involved in drug resistance, through increased phosphorylation of its intracytoplasmic domain and activation of PI3K/AKT signaling. In this paper we first show, by using a set of malignant pleural effusion derived cell cultures (MPEDCC) from patients with lung adenocarcinoma, that surface ErbB3 expression correlates with increased AKT phosphorylation. Antibodies against ErbB3, namely A3, which we previously demonstrated to induce receptor internalization and degradation, inhibit growth and induce apoptosis only in cells overexpressing surface ErbB3. Furthermore, combination of anti-ErbB3 antibodies with EGFR TKIs synergistically affect cell proliferation in vitro, cause cell cycle arrest, up-regulate p21 expression and inhibit tumor growth in mouse xenografts. Importantly, potentiation of gefitinib by anti-ErbB3 antibodies occurs both in de novo and in ab initio resistant cells. Anti-ErbB3 mAbs strongly synergize also with the dual EGFR and HER2 inhibitor lapatinib. Our results suggest that combination treatment with EGFR TKI and antibodies against ErbB3 should be a promising approach to pursue in the clinic.