Abstract B107: Targeting PI3K and mTOR with GDC-0980, a dual inhibitor, is efficacious in trastuzumab refractory and HER2+/PIK3CA-mutated breast cancer models
Authors: De Pradip , Sun Yuliang , Carlson Jennifer H. , Lin Xiaoqian , Lori Friedman , Dey Nandini , Leyland-Jones Brian 
Published: May 2016

Background: The PI3K-AKT-mTOR signaling plays an important role in breast cancer (BC). Its interaction with HER2 signaling becomes more complex and inter-dependent with acquired anti-HER2 therapy resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K-AKT-mTOR. Furthermore, BOLERO 1 study clearly showed that PFS was not significantly different between groups (combination of everolimus with trastuzumab (T) plus paclitaxel versus placebo with T plus paclitaxel, 14.95 versus 14.49 months) in the full analysis population. Dual blockade of PI3K/mTOR is therefore an attractive drug for HER2+ BC, especially in T-resistant and PIK3CAmutated conditions.

Methodology: Here we have studied the in vitro and in vivo effects of GDC-0980 in HER2+/T-sensitive (BT474), HER2+/T-resistant (BT474HerR), HER2+/PIK3CA (HCC1954, MDA-MB453) and HER2+/PTEN (HCC1569) mutated models. We assessed in vitro anti-proliferative, pro-apoptotic and activation status of the PI3K-AKT-mTOR signaling pathway following GDC-0980 treatment in HER2+ BC cell lines. We next evaluated the impact of GDC-0980 on tumor growth and angiogenesis using xenograft models.

Results: 1) GDC-0980 inhibited downstream activation of the PI3K-mTOR signaling pathway effectors, p-AKT (Ser473, The308), p-P70S6K, p-S6RP and p-4EBP1, 2) the anti-proliferative activity of GDC-0980 was observed by 3D-ON-TOP clonogenic assay, 3) consistent with anti-proliferative effects of GDC-0980, the proportion of cells in the G1 phase of the cell cycle increased in all three cell lines with a concomitant decrease in the S phase of their treatment with GDC-0980, 4) the initiation of apoptotic activity (annexin V) of GDC-0980 was significantly superior to that of an allosteric inhibitor of mTOR, RAD001. GDC-0980 also induced apoptotic markers like cleaved CASPASE3, cleaved PARP1, BIM in BT474, BT474HerR & HCC1954 BC cells and 5) in the HER2+/T-sensitive, HER2+/T-resistant and HER2+/PIK3CA mutated BC xenograft models, GDC-0980 inhibited PI3K signaling and had potent anti-tumor activity. Along with its anti-tumor effect, GDC-0980 effectively decreased tumor angiogenesis (tumor micro-vessel density via CD31 staining). These inhibitions were more pronounced when GDC-0980 was combined with T.

Conclusions: GDC-0980 inhibits the PI3K-AKT-mTORC1/C2 signaling pathway and results in anti-proliferative and anti-tumor activity in HER2+ breast cancer cells with both wild type and mutated PIK3CA.

Citation Format: Pradip De, Yuliang Sun, Jennifer H. Carlson, Xiaoqian Lin, Friedman Lori, Nandini Dey, Brian Leyland-Jones. Targeting PI3K and mTOR with GDC-0980, a dual inhibitor, is efficacious in trastuzumab refractory and HER2+/PIK3CA-mutated breast cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B107.