Abstract Estrogen positive (ER+) breast cancer accounts for the majority of all breast cancers and is primarily treated with endocrine therapy. However, even though current endocrine treatments are effective, a subset of patients inevitably become resistant to these treatments. The novel oral SERD, GDC-0810/ARN-810, is currently in Phase II clinical trials in ER+ breast cancer patients. GDC-0810 induces ERα degradation in ER+ MCF7 and T47D cells and inhibits cell proliferation. Moreover, it is also efficacious in ER+ tumor models in vivo, including in MCF7-ESR1 Y537S xenografts and in WHIM20 ESR1 mutant Y537S PDX tumors. Given that little is known about resistance mechanisms to SERDs, our aim was to understand what mechanisms may underlie resistance after continuous exposure. We generated cell lines resistant to GDC-0810 and show that all of these lines were also cross-resistant to fulvestrant and tamoxifen. We determined that cells with acquired-resistance were more sensitive than parental cells to inhibitors of the PI3K/AKT signaling pathway. Additionally, in some resistant clones, ERα protein expression was lost, but this loss was transient and could be regained after long-term growth in the absence of SERDs. A range of approaches are being undertaken to explore the underlying mechanisms driving acquired-resistance to SERDs. These preclinical studies may inform future clinical combinations. Citation Format: Christy Ong, Anneleen Daemen, Jason Oeh, Ellen Ingalla, Alfonzo Arrazate, Michelle Nanini, Deepak Sampath, Lori Friedman, Thomas O’Brien. Breast cancer cell lines with acquired resistance to selective ERα degraders (SERDs) are dependent on PI3K signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1803.