在多耐药性 HER2 阳性乳腺癌肺转移模型中比较曲妥珠单抗埃坦新、曲妥珠单抗德鲁司坦和地西他单抗维多汀的效果

IF 4.2 3区 医学 Q2 ONCOLOGY
Negar Pourjamal, Narjes Yazdi, Aleksi Halme, Vadim Le Joncour, Pirjo Laakkonen, Pipsa Saharinen, Heikki Joensuu, Mark Barok
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引用次数: 0

摘要

人表皮生长因子 2 (HER2) 阳性乳腺癌肺转移并对靶向药物产生耐药性是一个常见的治疗难题。缺乏对多种抗HER2靶向药物耐药的临床前肺转移模型阻碍了新型疗法的开发。我们通过将 JIMT-1 细胞注射到免疫缺陷 SCID 小鼠体内,建立了一种新型 HER2 阳性乳腺癌细胞系(L-JIMT-1),该细胞系来自肠外 JIMT-1 细胞系,具有形成肺转移瘤的高倾向性。所有注射了 L-JIMT-1 细胞的小鼠都出现了肺转移灶,与亲代 JIMT-1 细胞相比,肺转移灶出现得更快,数量也更多。L-JIMT-1 细胞比 JIMT-1 细胞表达更多的表皮生长因子受体和 HER2。L-JIMT-1 细胞对体外测试的所有五种酪氨酸激酶抑制剂(阿法替尼、厄洛替尼、拉帕替尼、沙比替尼和图卡替尼)都有抗药性。我们在体外比较了 JIMT-1 和 L-JIMT-1 对三种 HER2 靶向抗体-药物共轭物(ADC)曲妥珠单抗埃坦辛(T-DM1)、曲妥珠单抗德鲁司坦(T-DXd)和地西他单抗维多汀(DV)的敏感性、JIMT-1细胞对T-DXd耐药,对T-DM1部分敏感,对DV敏感,而L-JIMT-1细胞对T-DM1和T-DXd均耐药,但对DV中度敏感。在小鼠模型中,与载体相比,所有三种 ADC 都能抑制 L-JIMT-1 肺转移瘤的生长,但 DV 和 T-DXd 的抑制作用比 T-DM1 更强,而且 DV 治疗导致的肿瘤负荷最小。所建立的L-JIMT乳腺癌肺转移模型可能有助于评估治疗多耐药性HER2阳性晚期乳腺癌的抗癌药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model

Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model

Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.

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来源期刊
CiteScore
7.80
自引率
5.00%
发文量
55
审稿时长
12 months
期刊介绍: The Journal''s scope encompasses all aspects of metastasis research, whether laboratory-based, experimental or clinical and therapeutic. It covers such areas as molecular biology, pharmacology, tumor biology, and clinical cancer treatment (with all its subdivisions of surgery, chemotherapy and radio-therapy as well as pathology and epidemiology) insofar as these disciplines are concerned with the Journal''s core subject of metastasis formation, prevention and treatment.
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