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Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
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Drivers of AR indifferent anti-androgen resistance in prostate cancer cells

Florian Handle1, Stefan Prekovic1,2, Christine Helsen1

  • 1Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Scientific Reports
|September 26, 2019
PubMed

Insights

New prostate cancer models reveal resistance to anti-androgen therapies is driven by E2F hyper-activation, leading to cross-resistance with chemotherapy but sensitivity to PARP inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) treatment involves androgen receptor (AR) inhibition.
  • Resistance to AR signaling inhibitors develops in approximately 20% of mCRPC patients, often via AR-independent mechanisms.

Purpose of the Study:

  • To generate and characterize novel prostate cancer cell models exhibiting resistance to anti-androgen therapies and chemotherapy.
  • To elucidate the molecular drivers of AR-independent growth and cross-resistance in mCRPC.

Main Methods:

  • Generation of two anti-androgen and castration-resistant prostate cancer cell lines (AR-indifferent).
  • Assessment of drug sensitivity (anti-androgens, docetaxel, olaparib, obatoclax).
  • RNA-sequencing (RNA-seq) analysis to identify molecular alterations in resistant cell lines and mCRPC tissues.

Main Results:

  • The generated cell lines are resistant to AR signaling inhibitors and docetaxel, but sensitive to olaparib and obatoclax.
  • RNA-seq revealed hyper-activation of the E2F cell-cycle regulator as a driver of AR-indifferent growth.
  • E2F hyper-activation is linked to deregulation of cyclin D/E, E2F1, RB1, and increased Myc activity.
  • Similar alterations and increased E2F activity were observed in mCRPC tissue samples with low AR activity.

Conclusions:

  • The study presents two cellular models that mimic acquired AR-independent mCRPC phenotypes.
  • E2F hyper-activation is identified as a key mechanism driving AR-independent growth and chemotherapy cross-resistance.
  • These models offer valuable tools for studying treatment resistance and developing new therapeutic strategies for mCRPC.

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