title: Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models.
abstract: The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) pathway is a key pathway activated in castrate-resistant prostate cancer (CRPC). This preclinical study evaluates targeting of Akt with AZD5363 alone and in combination with enzalutamide (ENZ) to prevent and delay resistance. Our results demonstrate AZD5363 has significant proapoptotic, antiproliferative activity as monotherapy in ENZ-resistant cell lines in vitro and significantly decreased tumour growth in ENZ-resistant xenograft. The combination of AZD5363 and ENZ showed synergistic decreases in cell proliferation and induced cell-cycle arrest and apoptosis in prostate cancer cell lines LNCaP and C4-2. Notably, the combination of AZD5363 and ENZ resulted in an impressive regression of castrate-resistant LNCaP xenograft tumours without any recurrence demonstrated, whereas progression occurred with both monotherapies. Serum prostate-specific antigen (PSA) levels were also continuously suppressed, and nadir PSA levels were lower in the combination arm compared to ENZ alone. Combination AZD5363 and ENZ at time of castration similarly resulted in significant regression of tumours, with greater relative suppression of PSA compared to when administered to castrate-resistant xenografts. In summary, combination AZD5363 and ENZ significantly delays the development of ENZ resistance in preclinical models through synergistic increases in apoptosis and cell cycle arrest. Our results also suggest greater efficacy may be seen with earlier combination treatment. This study provides preclinical data to support evaluation of combination targeting of the PI3K/Akt pathway and the androgen-receptor axis in the clinic using AZD5363 and ENZ, respectively.
  
  
  RESULTS
  Targeting of the Akt and androgen receptor pathways with AZD5363 and enzalutamide, respectively, significantly delayed the development of enzalutamide-resistant prostate cancer through increased apoptosis and cell cycle arrest. This preclinical synergy provides a strong rationale for clinical evaluation of this combination.
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Toren
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Soojin
authors.initials: S
authors.lastname: Kim
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cordonnier
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address: azoubeidi@prostatecentre.com.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011467:Prostate / Q000166:cytology / Q000187:drug effects*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; 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: D001549:Benzamides; D009570:Nitriles; D011743:Pyrimidines; D011758:Pyrroles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; D051057:Proto-Oncogene Proteins c-akt; C575618:capivasertib
keywords: Akt inhibitor; Apoptosis; Enzalutamide; Prostate cancer