High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models

RB Marques, A Aghai, CMA de Ridder, D Stuurman… - European urology, 2015 - Elsevier
RB Marques, A Aghai, CMA de Ridder, D Stuurman, S Hoeben, A Boer, RP Ellston, ST Barry…
European urology, 2015Elsevier
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. Design, setting, and participants Twelve human …
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.
Design, setting, and participants
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.
Outcome measurements and statistical analysis
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.
Results and limitations
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.
Patient summary
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.
Elsevier