多激酶靶向治疗表达sfRon受体的卵巢肿瘤是一种有前景的治疗策略。

Q2 Biochemistry, Genetics and Molecular Biology
Genes and Cancer Pub Date : 2020-07-22 eCollection Date: 2020-12-31 DOI:10.18632/genesandcancer.205
Luyao Wang, Lin Wang, Magdalena Cybula, Ana Luiza Drumond-Bock, Katherine M Moxley, Magdalena Bieniasz
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引用次数: 0

摘要

sfRon激酶是卵巢癌的一个重要治疗靶点,它有助于肿瘤的生长和疾病的进展。我们推断,对sfRon通路的多激酶抑制可能是实现持续抗肿瘤反应的有效策略,同时防止治疗耐药性。我们在体外对sfRon信号进行了详细的解剖,并证明S6K1是表达sfRon的卵巢肿瘤多激酶靶向策略的关键组成部分。我们选择了AD80化合物靶向sfRon通路中的几种激酶,包括AKT和S6K1,并将其与选择性靶向sfRon或PI3激酶的抑制剂的效果进行了比较。通过使用人类卵巢异种移植物和临床相关的患者来源的异种移植物(PDXs),我们证明了单药AD80在体内治疗比标准治疗化疗(顺铂/紫杉醇)或BMS777607直接抑制sfRon激酶具有更好的疗效。我们的研究结果表明,同时靶向AKT和S6K1的多激酶抑制剂(如AD80)治疗表达sfRon的卵巢肿瘤最有效,可产生长期抗肿瘤反应并阻止转移发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Multi-kinase targeted therapy as a promising treatment strategy for ovarian tumors expressing sfRon receptor.

The sfRon kinase is an important therapeutic target in ovarian cancer that contributes to prominent tumor growth and disease progression. We reasoned that a multi-kinase inhibition of sfRon pathway might be an effective strategy to achieve a sustained anti-tumor response, while simultaneously preventing treatment resistance. We performed a detailed dissection of sfRon signaling in vitro and demonstrated that S6K1 is a key component of a multi-kinase targeting strategy in sfRon expressing ovarian tumors. We selected AD80 compound that targets several kinases within sfRon pathway including AKT and S6K1, and compared its efficacy with inhibitors that selectively target either sfRon or PI3 kinase. Using human ovarian xenografts and clinically relevant patient-derived xenografts (PDXs), we demonstrated that in vivo treatment with single agent AD80 shows superior efficacy to a standard-care chemotherapy (cisplatin/paclitaxel), or to the direct inhibition of sfRon kinase by BMS777607. Our findings indicate that ovarian tumors expressing sfRon are most effectively treated with multi-kinase inhibitors simultaneously targeting AKT and S6K1, such as AD80, which results in long-term anti-tumor response and prevents metastasis development.

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来源期刊
Genes and Cancer
Genes and Cancer Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.90
自引率
0.00%
发文量
6
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