Molecular Cancer Therapeutics 2015-01-01

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

Urs Hancox, Sabina Cosulich, Lyndsey Hanson, Cath Trigwell, Carol Lenaghan, Rebecca Ellston, Hannah Dry, Claire Crafter, Bernard Barlaam, Martina Fitzek, Paul D Smith, Donald Ogilvie, Celina D'Cruz, Lillian Castriotta, Stephen R Wedge, Lara Ward, Steve Powell, Mandy Lawson, Barry R Davies, Elizabeth A Harrington, Emily Foster, Marie Cumberbatch, Stephen Green, Simon T Barry

Index: Mol. Cancer Ther. 14(1) , 48-58, (2015)

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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 tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kβ and PI3Kδ (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor 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 < 1 μmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kβ with activity against PI3Kδ signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.©2014 American Association for Cancer Research.