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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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DDR kinase inhibition causes hypersensitivity to Taxol through caspase-3 activation

Megan Zaiger1, Junko Maeda1, Mami Murakami2

  • 1Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.

Biochemical and Biophysical Research Communications
|September 3, 2025
PubMed

Insights

Inhibiting DNA damage response (DDR) kinases enhances Taxol chemotherapy by increasing cancer cell death. This approach, targeting ATM, ATR, and DNA-PK, boosts Taxol

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Taxol (paclitaxel) is a key chemotherapy agent targeting cell cycle arrest.
  • PARP inhibition previously showed synergy with Taxol via oxidative stress.
  • DNA damage response (DDR) pathways are crucial for repairing chemotherapy-induced DNA damage.

Purpose of the Study:

  • To investigate if inhibiting DDR kinases enhances Taxol-induced cancer cell death.
  • To determine the role of specific DDR kinases (ATM, ATR, DNA-PK) in Taxol resistance.
  • To elucidate the mechanism of DDR inhibition-mediated sensitization to Taxol.

Main Methods:

  • Utilized Chinese hamster V79 cells and their ATM, ATR, and Ku80-deficient mutants.
  • Employed pharmacological inhibitors: KU55933 (ATM), NU7441 (DNA-PK), and VE821 (ATR).
  • Tested sensitization in V79, CHO, and U2OS human cancer cells; assessed apoptosis via sub-G1 analysis and caspase-3/7 assays. Investigated caspase-3 dependence using MCF7 and MCF7-C3 cells.

Main Results:

  • Inhibition of PI3K-like DDR kinases significantly enhanced Taxol-induced apoptosis.
  • ATM, ATR, and DNA-PK deficient cells showed hypersensitivity to Taxol.
  • Sensitization was dependent on caspase-3 activation, as shown by experiments with caspase-3 deficient/proficient cells.

Conclusions:

  • ATM, ATR, and DNA-PK kinases play a role in both DNA repair and suppressing Taxol-induced apoptosis.
  • Inhibiting these DDR kinases represents a potential strategy to improve Taxol efficacy.
  • Combined targeting of mitotic stress and DDR pathways could enhance Taxol and radiation therapy responses.
Keywords:
ATMATRCaspase-3DNA-PKTaxol

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