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Interaction between CDC6 and Tmod3 accelerates resistance to paclitaxel through focal adhesion assembly

Yue Liu1,2, Huirui Wang1, Jie Zhan1

  • 1Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, China.

Signal Transduction and Targeted Therapy
|December 3, 2025
PubMed

Insights

Cell division cycle 6 (CDC6) drives paclitaxel (PTX) resistance by regulating cell adhesion and the actin cytoskeleton. Depleting CDC6 sensitizes cancer cells to PTX, offering a new therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Paclitaxel (PTX) resistance and drug-tolerant persister cells limit its cancer treatment efficacy.
  • Identifying novel regulators of PTX resistance is crucial for improving therapeutic outcomes.

Purpose of the Study:

  • To systematically identify key regulators of paclitaxel resistance using a genome-wide screen.
  • To elucidate the novel mechanisms by which CDC6 confers PTX resistance.

Main Methods:

  • Genome-wide CRISPR/Cas9 knockout screen to identify resistance regulators.
  • Genetic depletion of CDC6 and assessment of PTX sensitivity.
  • Investigation of CDC6 interaction with Tmod3 and its role in cytoskeleton remodeling and focal adhesion assembly.
  • Combination treatment studies with PTX and actin filament inhibitors in vitro and in vivo.

Main Results:

  • Cell division cycle 6 (CDC6) was identified as a critical determinant of cell adhesion-mediated PTX resistance.
  • CDC6 functions through a novel pathway, distinct from known resistance mechanisms.
  • Genetic depletion of CDC6 significantly sensitized cells to PTX, increasing cell death.
  • CDC6 interacts with Tmod3, enhancing its stability and promoting drug resistance via actin cytoskeleton remodeling and focal adhesion assembly.
  • Combination therapy with PTX and actin inhibitors showed synergistic antitumor effects.

Conclusions:

  • CDC6 is a key regulator of PTX resistance, operating through cytoskeletal and adhesion pathways.
  • Targeting CDC6 or the cytoskeletal-adhesion axis presents a promising strategy to overcome PTX resistance and enhance cancer treatment efficacy.

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