Inhibition of PI3Kbeta signaling with AZD8186 inhibits growth of PTEN deficient breast and prostate tumour alone and in combination with docetaxel
Menée in vitro et in vivo, cette étude met en évidence l'activité antitumorale d'un composé appelé AZD8186, un inhibiteur de la signalisation PI3Kbeta, seul ou en combinaison avec du docétaxel, dans des tumeurs du sein triplement négatives et des tumeurs de la prostate n'exprimant pas PTEN
Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kβ isoform. Inhibitors of PI3Kβ have potential to reduce growth of tumours in which loss of PTEN drives tumour progression. We have developed a small molecule inhibitor of PI3Kβ and PI3Kδ (AZD8186) and assessed its anti-tumour activity across a panel of cell lines. We have then explored the anti-tumour effects as single agent and in combination with docetaxel in triple negative breast (TNBC) and prostate cancer models. In vitro AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI50≤1μM) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumours. Scheduling treatment with AZD8186 shows anti-tumour activity required only intermittent exposure, and that increased tumour control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kβ with activity against PI3Kδ signalling, and has potential to reduce growth of tumours dependent on dysregulated PTEN for growth. Moreover AZ8186 can be combined with docetaxel, a chemotherapy commonly used to treat advance TBNC and prostate tumours. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.
http://mct.aacrjournals.org/content/early/2014/11/14/1535-7163.MCT-14-0406.abstract 2014