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Abundant preclinical evidences indicate that stress-induced autophagy in tumor cells is predominantly cytoprotective and that inhibition of autophagy can enhance tumor cell death by diverse anticancer therapies. A major negative regulator of autophagy is the mammalian target of rapamycin (mTOR), activated downstream of PI3KAKT pathway. mTOR inhibitors, including rapamycin, have been shown to induce autophagy in tumor cells, while the combination of PI3K-AKT/mTOR and autophagy inhibitors shown synergistic effect on increased apoptosis and reduced autophagy (Takeuchi H. 2005). This project aimed to characterize the role of autophagy in Breast Cancer models exposed to new potent Genentech PI3K/AKT inhibitors GDC0068 (Ipatasertib) and GDC0032 (Taselisib) currently in phase III clinical trials on TNBC and ER+ patients. However, the efficacy of PI3K/AKT inhibitors may be limited by resistance mechanisms that result in minimal cell death in tumor cells. In order to investigate the role of autophagy as possible mechanisms of resistance, Ipatasertib and Taselisib have been evaluated in breast cancer cell lines characterized by different receptors profile: TNBC, HER2/c-erb-2 and luminal A cell lines. Our results showed that both drugs are able to induce G1/S cell cycle block and increase of autophagy signaling measured by p62 level and LC3 II/LC3 I ratio and by the percentage of cells exhibiting LC3 positive puncta. In addition, apoptosis increase was also evaluated by measuring positive annexin V staining, by flow cytometry technique, and apoptosis markers, such as PARP and cleaved caspase 3, by immunoblot assay. Furthermore, the supplement of pharmacologic inhibitors of autophagy, such as hydroxichloroquine, were able to reduce cell viability evaluated by both short- and long-term assays in cell lines exposed to Ipatasertib and Taselisib. 3D breast cancer models are ongoing to confirm the synergic effect of PI3K/AKT inhibitors and hydroxychloroquine, in order to provide a new therapeutic combinatorial approach potentially translatable to patients. Citation Format: Cocco S, Leone A, Buonfanti G, Sisalli MJ, Budillon A, De Laurentiis M. Role played by autophagy in breast cancer models exposed to new PI3K/AKT inhibitors, GDC-0068 and GDC-0032 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-09.