Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics.
Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics.
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DOI：
10.1016/j.jconrel.2017.12.024
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发表时间：
2018-02-10
期刊：
影响因子：
--
通讯作者：
Medina-Kauwe LK
中科院分区：
文献类型：
--
作者：
Sims JD;Taguiam JM;Alonso-Valenteen F;Markman J;Agadjanian H;Chu D;Lubow J;Abrol R;Srinivas D;Jain A;Han B;Qu Y;Mirzadehgan P;Hwang JY;Rentsendorj A;Chung A;Lester J;Karlan BY;Gray HB;Gross Z;Giuliano A;Cui X;Medina-Kauwe LK
抗肿瘤药物的耐药性是一个重要的临床问题。目前在临床上使用的肿瘤靶向治疗来自于减轻生长因子活性的抗体或小分子。与传统治疗方式相比，这些方法提高了治疗效果和安全性，但在大多数临床病例中会出现耐药性。靶向这种耐药性可以改善肿瘤减轻和患者生存。越来越多的此类肿瘤的特征在于细胞表面上人表皮生长因子受体3（HER3）的显著表达。这项研究提出了一种"特洛伊木马"方法，通过使用受体靶向的生物载体来对抗这些肿瘤，该生物载体利用HER3细胞表面蛋白作为门户，通过模拟必需配体将治疗剂潜入肿瘤细胞。这里使用的生物载体在单个融合蛋白中结合了几种功能，用于介导靶向细胞渗透和与治疗性货物的非共价自组装，形成HER3归巢纳米生物制剂。重要的是，我们在这里证明，这些纳米生物制剂在对临床批准的人EGF受体家族靶向抑制剂的耐药性的几种情况下是治疗有效的。我们还表明，这种抑制剂通过增加HER3表达来提高我们的纳米生物制剂对幼稚肿瘤的功效。这种方法利用了当前的临床问题（即对生长因子抑制的抗性），并使用它使肿瘤对HER3纳米生物治疗更敏感。此外，我们证明了一种解决耐药性的新方法，即通过使用耐药性产生的抑制剂并重新引入这些抑制剂作为佐剂，使肿瘤对本文所述的HER3纳米生物制剂敏感。
Resistance to anti-tumor therapeutics is an important clinical problem. Tumor-targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a “Trojan-Horse” approach to combating these tumors by using a receptor-targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non-covalent self-assembly with therapeutic cargo, forming HER3-homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naïve tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re-introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.1018001108
发表时间：
2012-02-21
影响因子：
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作者：
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通讯作者：
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