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Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical

Paul Toren1, Soojin Kim1, Thomas Cordonnier1

  • 1The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.

European Urology
|August 25, 2014
PubMed
Abstract

Insights

Combining AZD5363 with enzalutamide (ENZ) shows promise in preclinical prostate cancer models. This combination therapy effectively delays resistance and reduces tumor growth by increasing apoptosis and cell cycle arrest.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) pathway is frequently activated in castrate-resistant prostate cancer (CRPC).
  • Enzalutamide (ENZ) is a standard treatment for CRPC, but resistance often develops.
  • Targeting the PI3K/Akt pathway presents a potential strategy to overcome ENZ resistance.

Purpose of the Study:

  • To evaluate the efficacy of targeting Akt with AZD5363, alone and in combination with ENZ, in preclinical models of prostate cancer.
  • To determine if this combination can prevent or delay the development of ENZ resistance.
  • To investigate the underlying mechanisms of synergy between AZD5363 and ENZ.

Main Methods:

  • In vitro studies using prostate cancer cell lines (LNCaP and C4-2) resistant to ENZ.
  • In vivo studies using xenograft models of castrate-resistant prostate cancer.
  • Assessment of cell proliferation, apoptosis, cell-cycle arrest, tumor growth, and serum prostate-specific antigen (PSA) levels.

Main Results:

  • AZD5363 demonstrated significant proapoptotic and antiproliferative activity as monotherapy in ENZ-resistant cell lines and xenografts.
  • The combination of AZD5363 and ENZ exhibited synergistic effects, decreasing cell proliferation, inducing cell-cycle arrest, and promoting apoptosis.
  • Combination therapy led to significant regression of castrate-resistant xenograft tumors with no recurrence, unlike monotherapies.
  • Serum PSA levels were continuously suppressed with combination therapy, showing lower nadir levels compared to ENZ alone.
  • Earlier administration of the combination therapy at the time of castration resulted in greater tumor regression and PSA suppression.

Conclusions:

  • Combination therapy with AZD5363 and ENZ significantly delays the development of ENZ resistance in preclinical prostate cancer models.
  • The combination exerts synergistic effects through increased apoptosis and cell cycle arrest.
  • Earlier intervention with combination therapy may enhance efficacy.
  • These findings provide a strong preclinical rationale for clinical evaluation of combined PI3K/Akt and androgen receptor pathway inhibition.
Keywords:
Akt inhibitorApoptosisEnzalutamideProstate cancer

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