Abstract 2305: Targeting 6-phosphofructo-2-kinase to increase the efficacy of ER and CDK4/6 inhibitors against breast cancer

Abstract

Abstract We demonstrated that estradiol stimulates the expression and activity of an enzyme, 6-phosphofructo-2-kinase (PFKFB3), that regulates glucose metabolism via allosteric stimulation of 6-phosphofructo-1-kinase. PFKFB3 expression is increased in breast cancer cells that have metastasized to lymph nodes and the combination of the anti-estrogen, fulvestrant, with a PFKFB3 inhibitor, PFK158, synergistically increases apoptosis in ER+ breast cancer cells in vitro and in vivo. Given that estradiol simultaneously increases the expression of both the regulatory subunit of CDK4/6, cyclin D1, and PFKFB3, we postulated that the combination of palbociclib with PFK158 would yield synergy against breast cancer cells. In new preliminary studies, co-treatment with palbociclib and PFK158 resulted in a marked decrease in cell proliferation in two ER+ breast cancer cell lines that was accompanied by a synergistic decrease in phospho-Retinoblastoma (Rb). Importantly, exposure of ER+ breast cancer cells to palbociclib and PFK158 causes an increase in cell cycle arrest and apoptotic cell death in vitro. Notably, this combination has no effect on cell cycle arrest or apoptosis in normal mammary cells suggesting that this therapeutic strategy may be well tolerated and selective for breast cancer. Citation Format: Yoannis Imbert-Fernandez, Lilibeth Lanceta, Sucheta Telang, Jason Chesney. Targeting 6-phosphofructo-2-kinase to increase the efficacy of ER and CDK4/6 inhibitors against breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2305.