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Paclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell

Carin K Ingemarsdotter1, Laura A Tookman1, Ashley Browne1

  • 1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

Molecular Oncology
|January 7, 2015
PubMed

Insights

Paclitaxel-resistant ovarian cancer shows increased oncolytic adenovirus efficacy due to higher coxsackie adenovirus receptor (CAR) expression and altered cell cycle control. This finding may aid patient selection for future clinical trials.

Area of Science:

  • Oncology
  • Virology
  • Genetics

Background:

  • Ovarian cancer frequently develops resistance to paclitaxel chemotherapy.
  • Oncolytic adenoviruses represent a novel therapeutic strategy for malignancies.
  • Predictive biomarkers for oncolytic adenovirus activity in ovarian cancer are lacking.

Purpose of the Study:

  • To investigate the relationship between paclitaxel resistance and oncolytic adenovirus activity in ovarian cancer.
  • To identify potential biomarkers for predicting adenovirus efficacy in resistant ovarian cancer.
  • To explore the mechanisms underlying enhanced adenovirus activity in paclitaxel-resistant ovarian cancer.

Main Methods:

  • Utilized ovarian cancer cell line models and xenografts with acquired paclitaxel resistance.
  • Assessed the activity of multiple Ad5 adenovirus vectors (dl922-947, dl1520, Ad5 WT) in vitro and in vivo.
  • Analyzed coxsackie adenovirus receptor (CAR) expression, transcription, and histone modification.
  • Investigated adenovirus efficacy using group B adenoviruses (Ad11, Ad35) and CDK4/6 inhibition (PD-0332991).

Main Results:

  • Oncolytic Ad5 adenovirus activity was significantly increased in paclitaxel-resistant ovarian cancer.
  • Increased infectivity was linked to higher CAR expression, driven by histone modification in resistant cells.
  • Paclitaxel-resistant tumors showed increased CAR expression.
  • Dysregulated cell cycle control and enhanced efficacy of non-CAR-dependent adenoviruses were observed in resistant models.
  • CDK4/6 inhibition reversed paclitaxel resistance and reduced adenovirus efficacy.

Conclusions:

  • Paclitaxel resistance enhances oncolytic adenovirus efficacy through at least two mechanisms: increased CAR expression and altered cell cycle control.
  • Increased CAR expression in resistant cells is a result of epigenetic changes.
  • These findings suggest potential clinical utility for patient selection in oncolytic adenovirus trials.
Keywords:
AdenovirusCell cycle controlCoxsackie adenovirus receptorOvarian cancerPaclitaxel resistance

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