Abstract Alterations in the PI3K pathway are highly prevalent in triple-negative breast and high grade ovarian cancer, including BRCA1- and BRCA2-related disease. On the cellular level, loss of BRCA1 increases genomic instability and reliance on single strand break repair, hence creating an opportunity to treat BRCA-related TNBC or OC with PARP-inhibitors. In addition, loss of BRCA1 and/or p53 lead to relaxation of negative feed-back loops in mitogenic signaling, resulting in highly proliferative malignancies. For these reasons PARP-inhibitor Olaparib and PI3K-inhibitor NVP-BKM120 were tested in combination and found to be synergistic in mouse models of BRCA1-related BC. Surprisingly, PI3K-inhibition enhanced a DNA damage phenotype, caused by a profound decrease in DNA synthesis that could be observed after treatment with NVP-BKM120 in vivo and in vitro. The decrease in DNA synthesis was due to reduced Nucleoside synthesis resulting from a block in glycolysis that led to a drop in flux through the non-oxidative pentose phosphate pathway. In a preclinical mouse model (K14-Cre BRCA1f/fp53f/f), the combination of NVP-BKM120 and Olaparib could induce complete remissions, while PI3K-inhibitor alone marginally slowed disease progression and PARP-inhibitor alone stabilized the disease. This concept was translated into a clinical trial: BKM120/Olaparib for Triple Negative Breast Cancer or High Grade Serous Ovarian Cancer (NCT01623349; PI: Ursula Matulonis). Dose escalation for this study and accrual to an extension cohort at the MTD (NVP-BKM120 50 mg once a day in combination with Olaparib 300 mg twice a day) have been completed and a second dose escalation arm with NVP-BYL719 and Olaparib is ongoing. Citation Format: Gerburg M. Wulf, Ashish Juvekar, Costas M. Lyssiotis, Hai Hu, Kim Baek, Sina Yadegarynia, Ralph Scully, Eric Winer, John Asara, Lewis C. Cantley, Ursula Matulonis. Combination treatments that include PI3K-inhibitors for the treatment of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA21.