title: High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models.
abstract: BACKGROUND
  The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT pathway is frequently activated during prostate cancer (PCa) progression through loss or mutation of the phosphatase and tensin homolog (PTEN) gene. Following the androgen receptor (AR) pathway, it is the second major driver of PCa growth.
  
  
  OBJECTIVE
  To assess efficacy of novel PI3K/AKT-targeted therapies in PCa models, as a single agent and in combination with androgen deprivation.
  
  
  METHODS
  Twelve human PCa cell lines were tested in vitro for sensitivity to the AKT inhibitor AZD5363 and the PI3K beta/delta inhibitor AZD8186. The combination of AZD5363 and AZD8186 with castration was evaluated in vivo in PTEN-negative versus PTEN-positive patient-derived xenografts. Tumors and plasma were collected for biomarker analysis.
  
  
  METHODS
  In vitro growth inhibition was determined by methylthiazolyldiphenyl-tetrazolium bromide assay. In vivo efficacy was monitored by caliper measurements of subcutaneous tumor volume. PI3K/AKT and AR pathway activity was analyzed by Western blot, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction.
  
  
  CONCLUSIONS
  AZD5363 and AZD8186 inhibited in vitro growth of 10 of 12 and 7 of 12 PCa cell lines, respectively, with increased sensitivity under androgen depletion. In vivo, AZD5363 and AZD8186 as single agents significantly inhibited growth of PTEN-negative PC346C xenografts compared to placebo by 60% and 66%, respectively. Importantly, combination of either agent with castration resulted in long-lasting tumor regression, which persisted after treatment cessation. Expression of AR-target genes kallikrein-related peptidase 3 (KLK3, also known as PSA); transmembrane protease, serine 2 (TMPRSS2); and FK506 binding protein 5 (FKBP5) was upregulated after PI3K/AKT inhibition. Neither compound inhibited tumor growth in the PTEN-positive PC310 model.
  
  
  CONCLUSIONS
  Combination with hormonal therapy improved efficacy of PI3K/AKT-targeted agents in PTEN-negative PCa models. Upregulation of AR-target genes upon PI3K/AKT inhibition suggests a compensatory crosstalk between the PI3K-AR pathways. These data strongly advocate for further clinical evaluation.
  
  
  RESULTS
  Inactivation of the PTEN gene is a common event promoting prostate cancer (PCa) progression. This preclinical study illustrates the potent anticancer activity of novel PTEN-targeted drugs on PCa models, particularly in combination with hormonal therapy.
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. Electronic address: r.marques@erasmusmc.nl.
authors.forename: Rute B
authors.initials: RB
authors.lastname: Marques
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Aghai
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Corrina M A
authors.initials: CMA
authors.lastname: de Ridder
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Debra
authors.initials: D
authors.lastname: Stuurman
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Hoeben
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Agnes
authors.initials: A
authors.lastname: Boer
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Macclesfield, UK.
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Ellston
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Macclesfield, UK.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Macclesfield, UK.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Trapman
authors.affiliation: Department of Urology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002369:Castration / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C000595972:AZD8186; D000814:Aniline Compounds; D002867:Chromones; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D011944:Receptors, Androgen; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C575618:capivasertib
keywords: AKT inhibitor; Androgen receptor; PI3K inhibitor; Prostate cancer; Targeted therapy