While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

中文翻译：

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一种针对EGFR +和HER2 +癌症的新型蛋白毒性联合疗法。

尽管HER2和EGFR在乳腺癌和多种其他类型的肿瘤中过表达，但使用EGFR和/或HER2抑制剂未能治愈许多癌症患者，主要是因为癌症对HER2 / EGFR特异性药物产生了抗药性。过度表达HER家族蛋白EGFR，HER2和HER3的癌症对破坏HER2和EGFR蛋白折叠的药物具有独特的敏感性。我们以前表明二硫键破坏剂（DDA）破坏二硫键形成会通过多种机制杀死过表达HER2 / EGFR的细胞。在本文中，我们表明在HER2 / EGFR过表达细胞中脯氨酸异构化的干扰也诱导了癌细胞的死亡。肽基脯氨酰异构酶抑制剂环孢菌素A（CsA）通过激活caspase依赖性凋亡途径在体外选择性杀死EGFR +或HER2 +乳腺癌细胞。此外，CsA与DDA tcyDTDO协同作用以在体外杀死HER2 / EGFR过表达的细胞，而这两种药物在体内协同作用以杀死HER2 +肿瘤。迫切需要针对以目前可用的基于机制的药物耐药的靶向HER2 +和EGFR +癌症的新型策略。靶向HER2 / EGFR蛋白折叠的药物，包括DDA和CsA，具有通过诱导蛋白合成杀伤力来杀死过度表达EGFR或HER2的癌症的潜力。迫切需要针对以目前可用的基于机制的药物耐药的靶向HER2 +和EGFR +癌症的新型策略。靶向HER2 / EGFR蛋白折叠的药物，包括DDA和CsA，具有通过诱导蛋白合成杀伤力来杀死过度表达EGFR或HER2的癌症的潜力。迫切需要针对以目前可用的基于机制的药物耐药的靶向HER2 +和EGFR +癌症的新型策略。靶向HER2 / EGFR蛋白折叠的药物，包括DDA和CsA，具有通过诱导蛋白合成杀伤力来杀死过度表达EGFR或HER2的癌症的潜力。