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Updated: Jan 25, 2026

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
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Overexpressed ABCB1 Induces Olaparib-Taxane Cross-Resistance in Advanced Prostate Cancer

Alan P Lombard1, Chengfei Liu1, Cameron M Armstrong1

  • 1Department of Urologic Surgery, University of California Davis, 4860 Y Street, Suite 2200, Sacramento, CA 95817.

Translational Oncology
|May 11, 2019
PubMed

Insights

Poly (ADP-ribose) polymerase (PARP) inhibitors like olaparib show promise for prostate cancer. However, cross-resistance with therapies like docetaxel, mediated by ABCB1, can limit efficacy, necessitating new treatment strategies.

Area of Science:

  • Oncology
  • Cancer Therapeutics
  • DNA Damage Repair

Background:

  • Castration-resistant prostate cancer (CRPC) is an incurable malignancy.
  • Poly (ADP-ribose) polymerase (PARP) inhibitors are emerging as a therapeutic strategy for CRPC, particularly in patients with DNA repair defects.
  • The clinical trial TOPARP-A suggested olaparib efficacy in prostate cancer, but key questions regarding patient stratification, treatment sequencing, and cross-resistance persist.

Purpose of the Study:

  • To investigate potential cross-resistance between olaparib and existing therapies in treatment-resistant CRPC models.
  • To elucidate the mechanisms underlying cross-resistance, focusing on docetaxel and olaparib.
  • To identify strategies for overcoming cross-resistance and enhancing olaparib's therapeutic effectiveness.

Main Methods:

  • Development and utilization of docetaxel-resistant CRPC cell models.
  • Assessment of olaparib efficacy and mechanism of action (PARP trapping) in resistant models.
  • Evaluation of the role of ABCB1 (P-glycoprotein) in mediating cross-resistance.
  • Testing of combination therapies involving olaparib, enzalutamide, and ABCB1 inhibitors (elacridar).

Main Results:

  • Docetaxel-resistant CRPC cells displayed significant resistance to olaparib.
  • This cross-resistance was linked to diminished PARP trapping upon olaparib treatment.
  • Upregulated ABCB1 was identified as a key mediator of cross-resistance between taxanes and olaparib.
  • Inhibition of ABCB1 or reduction of its expression restored olaparib sensitivity.
  • Combining olaparib with enzalutamide demonstrated enhanced efficacy in olaparib-sensitive cells compared to monotherapy.

Conclusions:

  • Cross-resistance between olaparib and other CRPC therapies, such as docetaxel, can significantly impair treatment response.
  • ABCB1-mediated resistance is a critical factor that can be targeted to improve olaparib efficacy.
  • Combination strategies, including olaparib with enzalutamide or ABCB1 inhibitors, may overcome resistance and maximize therapeutic benefits in CRPC.

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