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Pim1激酶抑制剂通过下调HER2对HER2阳性乳腺癌细胞发挥抗癌活性。

Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2.

作者信息

Wang Bo-Wei, Huang Chih-Hao, Liu Liang-Chih, Cheng Fang-Ju, Wei Ya-Ling, Lin Yueh-Ming, Wang Yu-Fei, Wei Ching-Ting, Chen Yeh, Chen Yun-Ju, Huang Wei-Chien

机构信息

Graduate Institute of Biomedical Sciences, Center for Molecular Medicine and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.

Division of Breast Surgery, China Medical University Hospital, Taichung, Taiwan.

出版信息

Front Pharmacol. 2021 Jun 29;12:614673. doi: 10.3389/fphar.2021.614673. eCollection 2021.

DOI:10.3389/fphar.2021.614673
PMID:34267653
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8276059/
Abstract

The proviral integration site for moloney murine leukemia virus 1 (Pim1) is a serine/threonine kinase and able to promote cell proliferation, survival and drug resistance. Overexpression of Pim1 has been observed in many cancer types and is associated with the poor prognosis of breast cancer. However, it remains unclear whether Pim1 kinase is a potential therapeutic target for breast cancer patients. In this study, we found that Pim1 expression was strongly associated with HER2 expression and that HER2-overexpressing breast cancer cells were more sensitive to Pim1 inhibitor-induced inhibitions of cell viability and metastatic ability. Mechanistically, Pim1 inhibitor suppressed the expression of HER2 at least in part through transcriptional level. More importantly, Pim1 inhibitor overcame the resistance of breast cancer cells to HER2 tyrosine kinase inhibitor lapatinib. In summary, downregulation of HER2 by targeting Pim1 may be a promising and effective therapeutic approach not only for anti-cancer growth but also for circumventing lapatinib resistance in HER2-positive breast cancer patients.

摘要

莫洛尼氏鼠白血病病毒1原病毒整合位点（Pim1）是一种丝氨酸/苏氨酸激酶，能够促进细胞增殖、存活及耐药性。Pim1在多种癌症类型中均有过表达，且与乳腺癌的不良预后相关。然而，Pim1激酶是否为乳腺癌患者的潜在治疗靶点仍不清楚。在本研究中，我们发现Pim1表达与HER2表达密切相关，且HER2过表达的乳腺癌细胞对Pim1抑制剂诱导的细胞活力和转移能力抑制更为敏感。机制上，Pim1抑制剂至少部分通过转录水平抑制HER2的表达。更重要的是，Pim1抑制剂克服了乳腺癌细胞对HER2酪氨酸激酶抑制剂拉帕替尼的耐药性。总之，靶向Pim1下调HER2不仅可能是一种有前景且有效的抗癌生长治疗方法，还可能是克服HER2阳性乳腺癌患者对拉帕替尼耐药的有效方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb7f/8276059/4a06c9e3ab31/fphar-12-614673-g007.jpg
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