BioCentury
ARTICLE | Distillery Therapeutics

Cancer

December 19, 2018 8:48 PM UTC

Patient sample, cell culture and mouse studies suggest inhibiting the BRD4-FOXO3-CDK6 axis could help treat luminal breast cancer resistant to AKT inhibitors. In patients who had been treated for hormone receptor-positive luminal breast cancer, tumor levels of CDK6 protein were higher those with disease recurrence than those who remained disease-free. In three human luminal breast cancer cell lines, an siRNA targeting BRD4 increased sensitivity to the AKT inhibitor AZD5363 or two tool compound AKT inhibitors compared with a non-targeting siRNA. In one of the cell lines, an shRNA against the BRD4 binding partner FOXO3 increased sensitivity to one of the tool compounds. In a xenograft mouse model of luminal breast cancer, the same AKT inhibitor tool compound plus the CDK4/CDK6 inhibitor Ibrance palbociclib decreased tumor growth compared with either agent alone. Next steps could include testing BRD4 and FOXO3 inhibitors in mouse models of breast cancer resistant to AKT inhibitors.

AstraZeneca plc and Otsuka Pharmaceutical Co. Ltd. have AZD5363 in Phase II testing for breast cancer and Phase I testing for solid tumors...