Abstract LB-A02: AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells

Despite adjuvant anti-estrogen therapy for patients with ER+ breast cancer, clinically dormant residual disease can persist for years and eventually cause tumor recurrence. Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed clinically relevant xenograft models of dormancy induced by estrogen withdrawal. Dormant breast cancer cells exhibited upregulated AMPK levels and activity. Metformin is an AMPK-activating drug approved to treat diabetes that is being tested in many ongoing clinical trials for treatment of cancer. We found that metformin promoted survival of dormant ER+ breast cancer cells through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. These findings indicate that AMPK has context-dependent effects in cancer, caution against the widespread use of an AMPK activator across disease settings, and warrant the development of cancer therapeutics targeting fat metabolism. Citation Format: Riley Hampsch, Nicole Traphagen, Jason Wells, Charlotte McCleery, Jennifer Fields, Kevin Shee, Lloye Dillon, Darcy Pooler, Lionel Lewis, Eugene Demidenko, Yina Huang, Jonathan Marotti, William Kinlaw, Todd Wayne Miller. AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A02. doi:10.1158/1535-7163.TARG-19-LB-A02