AKT Inhibition Sensitizes to Polo-Like Kinase 1 Inhibitor Onvansertib in Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Polo-like kinase 1 (PLK1) inhibitors have shown limited success as monotherapies for cancer.
• Combination therapies are being explored to improve the efficacy of PLK1 inhibitors.
• Prostate cancer remains a significant health concern, necessitating novel therapeutic strategies.

Purpose of the Study:

• To identify effective combination therapies with the PLK1 inhibitor onvansertib (ONV).
• To evaluate the synergistic effects of ONV with AKT inhibitors in prostate cancer.
• To investigate the mechanistic basis for enhanced efficacy of combined ONV and AKT inhibition.

Main Methods:

• Screening of bioactive compounds in combination with ONV in LNCaP prostate cancer cells.
• In vitro synergy assays and apoptosis studies with ONV and ipatasertib (IPA).
• Mechanistic studies assessing SURVIVIN expression.
• In vivo efficacy studies in PTEN-deficient prostate cancer xenograft models.

Main Results:

• Onvansertib (ONV) enhanced responses to a PARP inhibitor (olaparib) in prostate cancer xenografts.
• Screening identified AKT inhibitors as effective partners for ONV.
• In vitro, the combination of ONV and ipatasertib (IPA) demonstrated synergy and increased apoptosis.
• Mechanistic studies revealed IPA mitigated ONV-induced SURVIVIN upregulation.
• Combination therapy with IPA and ONV significantly inhibited tumor growth in vivo.

Conclusions:

• The efficacy of PLK1 antagonists can be enhanced by co-administration with AKT or PARP inhibitors.
• Combination therapy with ipatasertib and onvansertib shows significant potential for prostate cancer treatment.
• These findings support further clinical development of PLK1 inhibitor combination strategies.