Exploiting proteotoxic stress in therapy-refractory HER2+ breast cancers

 描述(由申请人提供)：HER2靶向治疗HER2+癌症的益处有限，因为存在显著的从头和获得性耐药，并且对于难治性疾病的患者没有治疗选择。利用癌基因诱导的脆弱性作为癌症的治疗策略，已成为靶向驱动癌基因的一种有前途的替代方案。我们对临床数据集的初步电子分析和对细胞系的体外分析表明，HER2在乳腺上皮细胞中的过表达诱导了内质网(ER)中的蛋白毒性应激，而在HER2+的乳腺癌细胞中，由于ER相关降解(ERAD)复合体的特异性过表达，这种应激得到缓解。我们发现HER2+乳腺癌细胞强烈依赖ERAD来维持适当的蛋白质稳态和生存。因此，靶向ERAD在EGFR/HER2+乳腺癌细胞中选择性地诱导蛋白毒性内质网应激和细胞死亡，包括那些对曲妥珠单抗和拉帕替尼具有从头和获得性耐药的乳腺癌细胞。此外，我们发现ERAD的联合靶向和适应性内质网应激反应机制在诱导耐药的HER2+细胞的蛋白毒性内质网应激和细胞死亡方面可以协同作用。基于这些结果，我们认为致癌的HER2诱导的蛋白毒性内质网应激在临床上是一个显著的脆弱性，而强制不可恢复的蛋白毒性内质网应激的治疗靶向策略是对抗治疗难治的HER2+乳腺癌的有效方法。在这项建议中，我们建议1)确定HER2+细胞对ERAD上瘾的机制，2)确定最大化致癌内质网应激的新的有效组合策略，以及3)在体内测试在耐药乳腺癌中诱导致癌蛋白毒性应激的有效性。在目标3中，我们将利用患者来源的异种移植系，在小鼠体内肿瘤生长试验中测试几种新型ERAD抑制剂。

 DESCRIPTION (provided by applicant): Benefits of HER2-targeted therapy in HER2+ cancers are limited due to significant de novo and acquired resistance, and no therapy options exist for patients with refractory disease. Exploiting oncogene-induced vulnerabilities as a therapeutic strategy in cancers has emerged as a promising alternative to targeting of driver oncogenes. Our preliminary in silico analyses of clinical datasets and in vitro analyses on cell lines have revealed that HER2 overexpression in the mammary epithelial cells induces proteotoxic stress in the endoplasmic reticulum (ER), which is relieved in HER2+ breast cancer cells due to specific overexpression of the ER-associated degradation (ERAD) complex. We have found that HER2+ breast cancer cells are acutely dependent on ERAD to maintain proper protein homeostasis and survival. Accordingly, targeting of ERAD induces proteotoxic ER stress and cell death selectively in EGFR/HER2+ breast cancer cells, including those with de novo and acquired resistance to trastuzumab and lapatinib. In addition, we have found that combinatorial targeting of ERAD and adaptive ER stress response machinery can synergize in the induction of proteotoxic ER stress and cell death in drug- resistant HER2+ cells. Based on these results, we propose that oncogenic HER2-induced proteotoxic ER stress is a clinically significant vulnerability, and that the therapeutic targeting strategies to force irrecoverable proteotoxic ER stress are an effective approach against therapy-refractory HER2+ breast cancers. In this proposal, we propose to 1) identify the mechanisms of addiction of HER2+ cells to ERAD, 2) identify novel potent combinatorial strategies of maximizing oncogenic ER stress, and 3) test in vivo efficacy of inducing oncogenic proteotoxic stress in drug-resistant breast cancers. In Aim 3, we will test several novel inhibitors of ERAD in in vivo tumor growth assays in mice making use of patient- derived xenograft lines.