新型ErbB2靶向单抗在Trastuzumab耐药乳腺癌中的抗肿瘤作用及其机理

Trastuzumab, a humanized monoclonal antibody directed against ErbB2, was approved for treatment of ErbB2-overexpressing breast cancer in 1998. However, the therapeutic efficacy of trastuzumab remains modest, 70% of patients with ErbB2-overexpressing breast cancer do not respond to trastuzumab treatment. Overcoming trastuzumab resistance represents an important challenge to improving outcomes for patients with ErbB2-overexpressing breast cancer. In our previous studies, an anti-ErbB2 fully human antibody, denoted as H2-18, was isolated from a phage display antibody library. We surprisingly found that H2-18 potently induced programmed cell death (PCD) in ErbB2-overexpressing trastuzumab-resistant breast cancer cell lines. More importantly, H2-18 effectively inhibited the in vivo growth of ErbB2-overexpressing trastuzumab-resistant breast tumors. In the present study, we will investigate the molecular mechanism of how H2-18 induces PCD in ErbB2-overexpressing trastuzumab-resistant breast cancer cells. Moreover, we will study the antitumor effect of H2-18 on ErbB2-overexpressing trastuzumab-resistant breast cancer and elucidate its antitumor mechanism of action. We will also investigate the antitumor activity of H2-18 in combination with PI3K inhibitor in ErbB2-overexpressing trastuzumab-resistant breast cancer. This study may provide novel candidate antibody drugs for the treatment of ErbB2-overexpressing breast cancer and provide new strategies to develop more effective anti-ErbB2 therapeutic antibodies.

抗ErbB2人源化抗体Trastuzumab于1998年获批用于治疗ErbB2过表达乳腺癌。但临床数据显示其疗效还有所不足，约70%的ErbB2过表达乳腺癌患者对治疗不产生反应。因此，克服Trastuzumab耐药是临床上的迫切需求。近来，我们通过筛选全人源噬菌体抗体库获得了一株ErbB2单抗H2-18，我们惊奇地发现它能够强有力诱导Trastuzumab耐药乳腺癌细胞发生程序化死亡。更为重要的是， H2-18能够有效抑制Trastuzumab耐药乳腺癌在荷瘤小鼠体内的生长。在本项目中，我们将深入研究H2-18诱导乳腺癌细胞程序化死亡的作用机制，对H2-18在Trastuzumab耐药乳腺癌中的抗肿瘤作用进行研究并阐明其机理，还将探讨H2-18与PI3K抑制剂的联合抗肿瘤作用及机理。本项目的开展可能为乳腺癌的治疗提供候选抗体新药，并为设计更为有效的ErbB2靶向治疗性抗体提供新的思路。

抗ErbB2人源化抗体Trastuzumab于1998年获批用于治疗ErbB2过表达乳腺癌。但临床数据显示其疗效还有所不足，约70%的ErbB2过表达乳腺癌患者对治疗不产生反应。因此，克服Trastuzumab耐药是临床上的迫切需求。在前期研究中，我们通过筛选全人源噬菌体抗体库获得了一株ErbB2单抗H2-18。令人惊奇的是，H2-18强有力诱导Trastuzumab耐药乳腺癌细胞发生程序化死亡。更为重要的是，H2-18能够有效抑制Trastuzumab耐药乳腺癌在荷瘤小鼠体内的生长。在本项目中，我们深入研究了H2-18在Trastuzumab耐药乳腺癌中的抗肿瘤作用及其诱导乳腺癌细胞发生程序化死亡的分子机制。结果表明，H2-18不能抑制PI3K突变或PTEN丢失引起的PI3K/AKT信号的异常激活，但其可通过激活RIP1导致ROS产生，继而激活JNK通路诱导细胞发生程序化坏死。我们还研究了H2-18与PI3K抑制剂GDC-0941在Trastuzumab耐药乳腺癌中的联合抗肿瘤作用及机理。实验结果显示，H2-18与GDC-0941能够协同抑制Trastuzumab耐药乳腺癌细胞体外增殖。与单药相比，H2-18与GDC-0941联用具有显著增强的诱导乳腺癌细胞发生程序化死亡的能力。在Trastuzumab耐药乳腺癌荷瘤小鼠模型中，H2-18和GDC-0941联用组的抗肿瘤作用显著强于单药组。我们的数据提示H2-18和GDC-0941联用比单药具有更强抗肿瘤活性的原因可能主要由于联合用药可以更强地诱导肿瘤细胞发生程序化死亡。本项目的完成为乳腺癌的治疗提供了新的候选抗体新药，并为设计更为有效的ErbB2靶向抗体和治疗策略提供了新的思路。