Exploiting proteotoxic stress in therapy-refractory HER2+ breast cancers

 描述（由申请方提供）：由于显著的新发和获得性耐药，HER 2靶向治疗在HER 2+癌症中的获益有限，难治性疾病患者无治疗选择。利用癌基因诱导的脆弱性作为癌症的治疗策略已经成为靶向驱动癌基因的有希望的替代方案。我们对临床数据集的初步计算机分析和对细胞系的体外分析表明，乳腺上皮细胞中的HER 2过表达诱导内质网（ER）中的蛋白毒性应激，由于ER相关降解（ERAD）复合物的特异性过表达，这在HER 2+乳腺癌细胞中得到缓解。我们发现HER 2+乳腺癌细胞严重依赖ERAD来维持适当的蛋白质稳态和存活。因此，靶向ERAD选择性诱导EGFR/HER 2+乳腺癌细胞中的蛋白毒性ER应激和细胞死亡，包括对曲妥珠单抗和拉帕替尼具有新发和获得性耐药的那些。此外，我们已经发现ERAD和适应性ER应激反应机制的组合靶向可以协同诱导耐药HER 2+细胞中的蛋白毒性ER应激和细胞死亡。基于这些结果，我们提出致癌HER 2诱导的蛋白毒性ER应激是临床上显著的脆弱性，并且迫使不可恢复的蛋白毒性ER应激的治疗靶向策略是治疗难治性HER 2+乳腺癌的有效方法。在该提案中，我们建议1）确定HER 2+细胞对ERAD成瘾的机制，2）确定最大化致癌ER应激的新的有效组合策略，3）测试在耐药乳腺癌中诱导致癌蛋白毒性应激的体内功效。在目标3中，我们将在使用患者来源的异种移植物系的小鼠中的体内肿瘤生长测定中测试几种新型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.