Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN deficient breast and prostate tumour alone and in combination with docetaxel

Abstract

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.