Targeting CDK8 dually enhances paclitaxel antitumor efficacy and alleviates chemotherapy-induced peripheral neuropathy in breast cancer.

Authors

Xuejiao Hong, Dong Fang

Published in

Frontiers in pharmacology. Volume 17. Pages 1849893. Epub Jul 13, 2026.

Abstract

Paclitaxel-based chemotherapy remains a mainstay for breast cancer treatment, yet its efficacy is often limited by drug resistance and dose-limiting peripheral neuropathy. This study aimed to investigate whether CDK8 could serve as a dual target for enhancing the antitumor efficacy of paclitaxel while alleviating chemotherapy-induced neuropathic pain.
We evaluated CDK8 expression in human breast cancer specimens before and after paclitaxel-containing neoadjuvant chemotherapy, as well as in paclitaxel-treated breast cancer cell lines and DRGs from syngeneic tumor-bearing mice. Loss- and gain-of-function approaches were performed to assess the functional role of CDK8 in tumor growth, paclitaxel sensitivity, and neuropathic pain behaviors. Myelin damage in the sciatic nerve was evaluated by transmission electron microscopy via G-ratio quantification. Finally, the selective CDK8/CDK19 inhibitor romaciclib was tested for its ability to enhance paclitaxel antitumor efficacy and alleviate paclitaxel induced peripheral neuropathy in a 4T1 murine breast cancer model.
CDK8 expression was markedly upregulated in human post-chemotherapy breast cancer tissues, paclitaxel-treated breast cancer cells, and DRGs of tumor-bearing mice. CDK8 overexpression promoted tumor growth and paclitaxel resistance, while CDK8 knockdown sensitized tumors to chemotherapy. In the peripheral nervous system, elevated CDK8 in DRGs recapitulated paclitaxel-induced mechanical allodynia, thermal hyperalgesia, and myelin damage, whereas CDK8 depletion prevented these neurotoxic effects. Pharmacological inhibition of CDK8 with romaciclib not only enhanced the antitumor efficacy of paclitaxel but also significantly alleviated paclitaxel-induced peripheral neuropathy in vivo.
CDK8 is a dual target linking chemoresistance and neurotoxicity. Inhibiting CDK8 with romaciclib may improve paclitaxel therapy while reducing its side effects.

PMID:
42516564
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.

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