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Ref Type Journal Article
PMID (38894678)
Authors Nouri M, Varkaris A, Ridinger M, Dalrymple SL, Dennehy CM, Isaacs JT, Einstein DJ, Brennen WN, Balk SP
Title AKT Inhibition Sensitizes to Polo-Like Kinase 1 Inhibitor Onvansertib in Prostate Cancer.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 23 10 2024 Oct 01 1404-1417 Mol Cancer Ther
URL
Abstract Text Polo-like kinase 1 (PLK1) inhibitors have had limited antitumor efficacy as single agents, and focus of current efforts is on combination therapies. We initially confirmed that the PLK1-specific inhibitor onvansertib (ONV) could enhance responses to a PARP inhibitor (olaparib) in prostate cancer xenografts. To identify more effective combinations, we screened a library of bioactive compounds for efficacy in combination with ONV in LNCaP prostate cancer cells, which identified a series of compounds including multiple AKT inhibitors. We confirmed in vitro synergy between ONV and the AKT inhibitor ipatasertib (IPA) and found that the combination increased apoptosis. Mechanistic studies showed that ONV increased expression of the antiapoptotic protein SURVIVIN and that this was mitigated by IPA. Studies in three PTEN-deficient prostate cancer xenograft models showed that cotreatment with IPA and ONV led to significant tumor growth inhibition compared with monotherapies. Together, these in vitro and in vivo studies demonstrate that the efficacy of PLK1 antagonists can be enhanced by PARP or AKT inhibition and support further development of these combination therapies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss prostate cancer sensitive Ipatasertib + Onvansertib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of Ipatasertib (GDC-0068) and Onvansertib (PCM-075) resulted in greater tumor growth inhibition compared to either therapy alone in PTEN-deficient prostate cancer cell line xenograft models (PMID: 38894678). 38894678