Targeting DKK1 enhances the antitumor activity of paclitaxel and alleviates chemotherapy-induced peripheral neuropathy in breast cancer.

Autor: Shi HX; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China.; Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng, 475004, China., Tao HT; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China., He JJ; Department of Pharmacy, The First Affiliated Hospital of Henan University, Kaifeng, 475004, China., Zhu FY; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China., Xie CQ; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China., Cheng YN; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China., Hou LL; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China., Sun H; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China., Qin CJ; Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng, 475004, China. hhyyqcj@163.com., Fang D; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China. fangdong@henu.edu.cn.; Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng, 475004, China. fangdong@henu.edu.cn., Xie SQ; Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China. xiesq@henu.edu.cn.; Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng, 475004, China. xiesq@henu.edu.cn.
Jazyk: angličtina
Zdroj: Molecular cancer [Mol Cancer] 2024 Jul 31; Vol. 23 (1), pp. 152. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1186/s12943-024-02067-y
Abstrakt: Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8 + T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.
(© 2024. The Author(s).)
Databáze: MEDLINE
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