Noto Alessia, De Vitis Claudia, Roscilli Giuseppe, Fattore Luigi, Malpicci Debora, Marra Emanuele, Luberto Laura, D'Andrilli Antonio, Coluccia Pierpaolo, Giovagnoli Maria Rosaria, Normanno Nicola, Ruco Luigi, Aurisicchio Luigi, Mancini Rita, Ciliberto Gennaro
Dipartimento di Medicina Clinica e Molecolare, Sapienza Universita' di Roma, Italy.
Oncotarget. 2013 Aug;4(8):1253-65. doi: 10.18632/oncotarget.1141.
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.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂吉非替尼和厄洛替尼的引入，改善了晚期非小细胞肺癌（NSCLC）的个体化治疗。EGFR酪氨酸激酶抑制剂能在具有EGFR胞质酪氨酸激酶结构域敏感突变的患者中诱导显著的客观反应并延长生存期。然而，几乎所有患者都会产生耐药性，这导致了疾病复发。因此，人们正在进行多项研究以了解耐药机制，从而开发出能使耐药细胞对EGFR酪氨酸激酶抑制剂敏感的联合治疗方案。最近的研究表明，EGFR受体家族的另一个成员ErbB3的上调通过其胞质结构域磷酸化增加和PI3K/AKT信号通路激活参与了耐药过程。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ErbB3表达与AKT磷酸化增加相关。抗ErbB3抗体，即A3，我们之前证明它能诱导受体内化和降解，仅在表面ErbB3过表达的细胞中抑制生长并诱导凋亡。此外，抗ErbB3抗体与EGFR酪氨酸激酶抑制剂联合在体外协同影响细胞增殖，导致细胞周期停滞，上调p21表达并抑制小鼠异种移植瘤的生长。重要的是，抗ErbB3抗体对吉非替尼的增效作用在原发性和初始耐药细胞中均会出现。抗ErbB3单克隆抗体也与EGFR和HER2双重抑制剂拉帕替尼强烈协同。我们的结果表明，EGFR酪氨酸激酶抑制剂与抗ErbB3抗体联合治疗应是临床上一种有前景的治疗方法。
