Abstract 5553: Monotherapy efficacy of catalytic and allosteric inhibitors of AKT in breast cancer models with AKT1E17K mutations

Abstract

Abstract AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1E17K mutation is not known. Expression of exogenous copies of AKT1E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, and induced colony formation in soft agar. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. We identified two breast cancer explant models with AKT1E17K mutation (HBC-x2 and HBCx-31). Dosing of AZD5363 at 150 mg/kg twice daily or MK-2206 at 120 mg/kg 3 times a week significantly inhibited tumor growth in both models, but AZD5363 was significantly more active than MK-2206 at the dosing schedules employed, in both models. Pharmacodynamics were assessed in the HBC-x2 model at 2 h after the final dose. Both compounds significantly inhibited phosphorylation of PRAS40 and S6, caused relocalisation of FOXO3a to the nucleus, and reduced Ki67 staining. The data indicate that breast cancers with AKT1E17K mutations are rational targets for monotherapy treatment with AKT inhibitors. Citation Format: Barry R. Davies, Nin Guan, Armelle Logie, Amy Palmer, Vivien Jacobs, Neil James, Emma L. Jenkins. Monotherapy efficacy of catalytic and allosteric inhibitors of AKT in breast cancer models with AKT1E17K mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5553. doi:10.1158/1538-7445.AM2014-5553