Authors
Kai Wang, Yuqing Yuan, Wei Shen, Xiuxiu Yang, Xiaokang Wu, Haihua Zhou, Yi Hu, Qing Zhu
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e20089. Jul 30, 2026. Epub Jul 30, 2026.
Abstract
Breast cancer remains one of the most prevalent malignancies among women, and taxane-based chemotherapies such as paclitaxel and docetaxel are central to standard treatment regimens. However, drug resistance in breast cancer limits therapeutic efficacy and contributes to recurrence and metastasis. Identifying resistance-associated molecular targets is therefore critical for advancing treatment strategies. To investigate paclitaxel resistance, we designed and synthesized four paclitaxel-derived probes. Among these, PTX-4, constructed via a stable C─C bond linkage, exhibited superior efficiency. Using a chemoproteomic approach, we systematically profiled paclitaxel-binding proteins in parental and resistant breast cancer cells. This strategy successfully identified AKT2, an unrecognized paclitaxel-interacting protein in paclitaxel-resistant breast cancer. Functional validation demonstrated that AKT2 is a direct target of paclitaxel in paclitaxel-resistant cells. Knockdown and pharmacological inhibition of AKT2 restored the sensitivity of paclitaxel-resistant cells to paclitaxel. These findings establish AKT2 as a key mediator of paclitaxel resistance in breast cancer. Targeting AKT2 may offer a promising therapeutic strategy to overcome resistance and improve the clinical efficacy of taxane-based chemotherapy. This study highlights the advantage of C─C bond-linked, pharmacologically active probes for chemoproteomic profiling of drug targets.
PMID:
42531596
Bibliographic data and abstract were imported from PubMed on 31 Jul 2026.
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