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Leveraging a Multienzymes-Mimicking Nanozyme to Overcome CDK4/6 Inhibitor Resistance and Achieve Drug Repurposing in

Peilin Wu1, Ling Lan2, Zihan Li1

  • 1Department of Laboratory Medicine/Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Small (Weinheim an Der Bergstrasse, Germany)
|April 8, 2026
PubMed

Insights

New nanozyme therapy overcomes drug resistance in esophageal cancer by targeting cell metabolism and apoptosis pathways. This approach synergizes with CDK4/6 inhibitors, showing potent antitumor effects and offering potential for precision medicine.

Area of Science:

  • Oncology
  • Biotechnology
  • Materials Science

Background:

  • Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors show promise for esophageal squamous cell carcinoma (OSCC) due to cell cycle alterations.
  • Clinical trials reveal significant drug resistance challenges in OSCC treatment with CDK4/6 inhibitors.

Purpose of the Study:

  • To investigate the mechanisms of CDK4/6 inhibitor resistance in OSCC.
  • To develop a novel therapeutic strategy to overcome this resistance and enhance antitumor efficacy.

Main Methods:

  • Investigated CDK4/6 inhibitor effects on pan-ERBB pathway and GPX4 expression.
  • Developed a nanozyme (Pd/s-CALDH@Palbo) loaded with CDK4/6 inhibitors.
  • Evaluated nanozyme efficacy in vitro and in vivo for suppressing resistance pathways and inducing cell death.

Main Results:

  • CDK4/6 inhibitors induced pan-ERBB pathway activation and GPX4 overexpression, promoting metabolism and reducing apoptosis/ferroptosis sensitivity.
  • The developed nanozyme suppressed these resistance mechanisms.
  • Nanozyme treatment effectively triggered apoptosis and ferroptosis, overcoming resistance and demonstrating significant antitumor activity in OSCC models.

Conclusions:

  • Nanozyme-mediated drug repurposing offers a novel strategy to overcome CDK4/6 inhibitor resistance in OSCC.
  • The developed Pd/s-CALDH@Palbo nanozyme shows potent antitumor efficacy by modulating cellular metabolism and inducing cell death.
  • This approach holds potential for precision medicine applications in OSCC treatment.
Keywords:
CDK4/6 inhibitordrug repurposingdrug resistancenanozymeoesophageal cancer

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