Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
Cancer Sci. 2018 Jun;109(6):1949-1957. doi: 10.1111/cas.13593. Epub 2018 May 7.
Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors have been developed recently and have shown efficacy in breast cancer as a single agent or in combination with anti-HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established an Src inhibitor saracatinib-resistant breast cancer cell line (SKBR-3/SI) for the first time and by evaluating mRNA expression profile, we found that plasminogen activator inhibitor-1 (PAI-1) was upregulated in saracatinib-resistant cells compared to the parent cells. Further study demonstrated that PAI-1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of chemokine (C-C motif) ligand 5 (CCL5). Functional assays showed that PAI-1 and CCL5 overexpression promoted cell proliferation and migration in breast cancer cells, while inhibition of PAI-1 and CCL5 decreased cell proliferation and migration in saracatinib-resistant cells. We also showed that targeting PAI-1 or CCL5 could reverse saracatinib resistance, which deserves more attention in clinical settings.
酪氨酸激酶Src 在包括乳腺癌在内的各种肿瘤中过表达和激活，被认为促进了癌症的形成和发展。最近已经开发出了Src 抑制剂，并且作为单一药物或与抗 HER2 抗体或化疗联合使用，在乳腺癌中显示出疗效。不幸的是，Src 抑制剂的效力受到耐药性发展的限制。在我们的研究中，我们首次建立了 Src 抑制剂 saracatinib 耐药的乳腺癌细胞系（SKBR-3/SI），通过评估 mRNA 表达谱，我们发现与亲本细胞相比，纤溶酶原激活物抑制剂-1（PAI-1）在 saracatinib 耐药细胞中上调。进一步的研究表明，PAI-1 可能通过增加趋化因子（C-C 基序）配体 5（CCL5）的分泌来诱导乳腺癌细胞中的 saracatinib 耐药。功能测定表明，PAI-1 和 CCL5 的过表达促进了乳腺癌细胞的增殖和迁移，而 PAI-1 和 CCL5 的抑制减少了 saracatinib 耐药细胞的增殖和迁移。我们还表明，靶向 PAI-1 或 CCL5 可以逆转 saracatinib 耐药，这在临床环境中值得更多关注。
