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Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
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Intracrine androgen biosynthesis and drug resistance

Trevor M Penning1, Irfan A Asangani2, Cynthia Sprenger3

  • 1Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Cancer Drug Resistance (Alhambra, Calif.)
|May 18, 2022
PubMed

Insights

Androgen receptor signaling inhibitors (ARSI) are used for prostate cancer but resistance develops. This review explores how intracrine androgen biosynthesis drives ARSI resistance and discusses strategies to overcome it.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Castration-resistant prostate cancer (CRPC) is lethal and often relies on androgen receptor (AR) signaling.
  • Current therapies like abiraterone acetate and enzalutamide target AR signaling but face rapid drug resistance.
  • Resistance mechanisms include AR mutations, structural changes, and altered androgen metabolism.

Purpose of the Study:

  • To review the role of intracrine androgen biosynthesis in ARSI drug resistance in CRPC.
  • To discuss therapeutic strategies to overcome ARSI resistance driven by intracrine mechanisms.

Main Methods:

  • Literature review of studies on CRPC, AR signaling, and drug resistance.
  • Focus on mechanisms of intracrine androgen biosynthesis and metabolism.
  • Analysis of therapeutic approaches targeting these resistance pathways.

Main Results:

  • Intracrine androgen biosynthesis within tumors can sustain AR signaling despite ARSI treatment.
  • This adaptive biosynthesis is a key mechanism contributing to acquired resistance to abiraterone and enzalutamide.
  • Targeting intracrine pathways offers potential to resensitize tumors to ARSI therapy.

Conclusions:

  • Intracrine androgen biosynthesis is a critical driver of resistance to ARSI in CRPC.
  • Developing therapies that inhibit intracrine androgen production or metabolism is essential to improve CRPC treatment outcomes.
  • Combination strategies targeting both AR signaling and intracrine biosynthesis may overcome resistance.
Keywords:
Prostate cancerabiraterone acetatealdo-keto reductase 1C3androgen biosynthesisenzalutamide

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