Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells.
Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells.
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DOI：
10.18632/oncotarget.15952
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发表时间：
2017-04-25
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影响因子：
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通讯作者：
Law BK
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文献类型：
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作者：
Ferreira RB;Wang M;Law ME;Davis BJ;Bartley AN;Higgins PJ;Kilberg MS;Santostefano KE;Terada N;Heldermon CD;Castellano RK;Law BK
许多乳腺癌死亡是由于肿瘤对现有疗法产生耐药性。因此，需要新的治疗剂来靶向耐药乳腺癌。药物难治性乳腺癌包括对HER 2靶向抗体和激酶抑制剂具有获得性抗性的HER 2+肿瘤，以及缺乏治疗靶标雌激素受体、孕激素受体和HER 2的“三阴性”乳腺癌（TNBC）。显著部分的TNBC过表达HER 2家族成员表皮生长因子受体（EGFR）。因此，选择性杀死EGFR+和HER 2+肿瘤的药物将为乳腺癌治疗提供新的选择。我们先前鉴定了一类我们称为二硫键破坏剂（DDA）的化合物，其在体外选择性地杀死EGFR+和HER 2+乳腺癌细胞，并在动物模型中阻断HER 2+乳腺肿瘤的生长。发现DDA依赖性细胞毒性与HER 1 -3和Akt去磷酸化的下调相关。在这里，我们证明了DDA激活未折叠蛋白反应（UPR），这在其杀死EGFR+和HER 2+癌细胞的能力中发挥作用。使用异位表达EGFR或HER 2的乳腺癌细胞系和UPR的药理学探针揭示了所有三种DDA反应：HER 1 -3下调、Akt去磷酸化和UPR活化，有助于DDA介导的细胞毒性。值得注意的是，EGFR过表达增强了这些反应中的每一种。与DDA的联合研究表明，它们可能与EGFR/HER 2特异性受体酪氨酸激酶抑制剂和mTORC 1抑制剂互补，以克服耐药性。
Many breast cancer deaths result from tumors acquiring resistance to available therapies. Thus, new therapeutic agents are needed for targeting drug-resistant breast cancers. Drug-refractory breast cancers include HER2+ tumors that have acquired resistance to HER2-targeted antibodies and kinase inhibitors, and “Triple-Negative” Breast Cancers (TNBCs) that lack the therapeutic targets Estrogen Receptor, Progesterone Receptor, and HER2. A significant fraction of TNBCs overexpress the HER2 family member Epidermal Growth Factor Receptor (EGFR). Thus agents that selectively kill EGFR+ and HER2+ tumors would provide new options for breast cancer therapy. We previously identified a class of compounds we termed Disulfide bond Disrupting Agents (DDAs) that selectively kill EGFR+ and HER2+ breast cancer cells in vitro and blocked the growth of HER2+ breast tumors in an animal model. DDA-dependent cytotoxicity was found to correlate with downregulation of HER1-3 and Akt dephosphorylation. Here we demonstrate that DDAs activate the Unfolded Protein Response (UPR) and that this plays a role in their ability to kill EGFR+ and HER2+ cancer cells. The use of breast cancer cell lines ectopically expressing EGFR or HER2 and pharmacological probes of UPR revealed all three DDA responses: HER1-3 downregulation, Akt dephosphorylation, and UPR activation, contribute to DDA-mediated cytotoxicity. Significantly, EGFR overexpression potentiates each of these responses. Combination studies with DDAs suggest that they may be complementary with EGFR/HER2-specific receptor tyrosine kinase inhibitors and mTORC1 inhibitors to overcome drug resistance.