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Inhibition of Serum Response Factor Improves Response to Enzalutamide in Prostate Cancer

R William Watson1, Haleema Azam2,3, Claudia Aura2,3

  • 1Conway Institute of Biomolecular and Biomedical Research, UCD School of Medicine, University College Dublin, Belfield, D4, Dublin, Ireland.

Cancers
|December 2, 2020
PubMed

Insights

Targeting serum response factor (SRF) with inhibitors like CCG1423 can improve treatment outcomes for castrate-resistant prostate cancer (CRPC). SRF inhibition enhances enzalutamide response and reduces tumor growth by affecting androgen receptor localization.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Castrate-resistant prostate cancer (CRPC) poses treatment challenges due to androgen receptor (AR) mediated resistance.
  • Understanding AR co-regulator interactions is crucial for developing novel therapeutic strategies against CRPC.
  • Serum response factor (SRF) was previously identified as a potential therapeutic target in CRPC, with high expression linked to poorer patient survival.

Purpose of the Study:

  • To evaluate the efficacy of serum response factor (SRF) inhibition as a therapeutic strategy in castrate-resistant prostate cancer (CRPC).
  • To assess the combined effect of SRF inhibition and enzalutamide treatment in preclinical models of CRPC.
  • To investigate the association between SRF expression and response to enzalutamide therapy in CRPC patients.

Main Methods:

  • In vitro and in vivo experiments using CRPC models.
  • Treatment with the SRF inhibitor CCG1423, alone and in combination with enzalutamide.
  • Assessment of AR nuclear localization, alpha-tubulin acetylation, prostate-specific antigen (PSA) levels, and tumor volume.
  • Immunohistochemical analysis of SRF expression in metastatic CRPC patient tissues.

Main Results:

  • SRF inhibition with CCG1423 enhanced enzalutamide efficacy in vitro.
  • CCG1423 treatment reduced tumor volume in a CRPC patient-derived xenograft model.
  • SRF inhibition decreased AR nuclear localization and alpha-tubulin acetylation in vitro, and reduced PSA levels in vivo.
  • High SRF expression in metastatic CRPC tissues correlated with a shorter response duration to enzalutamide.

Conclusions:

  • Serum response factor (SRF) is a viable therapeutic target for overcoming enzalutamide resistance in CRPC.
  • SRF inhibitors, such as CCG1423, show promise in combination therapy to improve treatment outcomes for CRPC patients.
  • Targeting SRF may represent a novel approach to enhance the effectiveness of current therapies for advanced prostate cancer.
Keywords:
androgen receptorenzalutamideprostate cancerserum response factor

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