Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

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.