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Overcoming PLK1 inhibitor resistance by targeting mevalonate pathway to impair AXL-TWIST axis in colorectal cancer

Sonia Solanes-Casado1, Arancha Cebrián1, María Rodríguez-Remírez2

  • 1Translational Oncology Division, Oncohealth Institute, IIS - Fundación Jiménez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|October 26, 2021
PubMed

Insights

Drug resistance to Polo Like Kinase1 (PLK1) inhibitors in colorectal cancer can be overcome. Simvastatin re-sensitizes resistant cells by targeting the mevalonate pathway, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Colorectal cancer (CRC) treatment faces challenges with drug resistance to Polo Like Kinase1 (PLK1) inhibitors.
  • Developing strategies to overcome PLK1 inhibitor resistance is crucial for improving metastatic CRC patient outcomes.

Purpose of the Study:

  • To investigate mechanisms of BI2536 resistance in colorectal cancer cell lines.
  • To identify potential re-sensitizing agents and combination therapies to overcome PLK1 inhibitor resistance.

Main Methods:

  • Generated and validated BI2536-resistant colorectal cancer cell lines (HT29R, RKO_R, SW837R, HCT116R).
  • Sequenced PLK1 gene, analyzed AXL pathway, Epithelial-to-Mesenchymal transition (EMT), and Multidrug Resistance (MDR1) via qPCR and Western blot.
  • Tested simvastatin as a re-sensitizer and evaluated combination strategies in vitro and in vivo.

Main Results:

  • Identified PLK1 gene mutation R136G in RKO_R cells.
  • Discovered AXL pathway activation via TWIST1, leading to EMT and MDR1 upregulation in HT29R, SW837R, and HCT116R cells.
  • Simvastatin re-sensitized resistant cells by inhibiting adaptive resistance mechanisms, restoring sensitivity to BI2536 in vitro and in vivo.

Conclusions:

  • The AXL pathway and EMT contribute to PLK1 inhibitor resistance in CRC.
  • Simvastatin targets the mevalonate pathway to overcome adaptive resistance.
  • Combination therapy with simvastatin and PLK1 inhibitors presents a promising strategy for managing resistant colorectal cancer.
Keywords:
BI2536Colorectal cancer (CRC)Drug resistancePolo-Like Kinase 1 (PLK1)Re-sensitizationSimvastatin

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