Abstract 4717: In vitro potency of dual PI3K/mTORC1/C2 inhibitor, GDC-0980 in ER+ and HER2 overexpressing breast cancer cells

Abstract

Abstract Background: Persistent activation of the PI3K-AKT-mTORC1/C2 signaling pathway drives aberrant cell growth and proliferation in a variety of tumor types including breast tumors. Recent works have demonstrated a strong association between mutational activation of PIK3CA or loss of function of PTEN and resistance to therapies targeted against the ER or HER2 pathway. Purpose: Since the PI3K-AKT-mTORC1/C2 is one of the major cell survival pathways responsible for the progression of breast cancer and appears to be upregulated during development of the resistance to endocrine and trastuzumab treatments suppression of this pathway by administration of GDC-0980 may therefore be efficacious in ER+ and HER2+ breast cancer models. Experimental Design: To examine this possibility, GDC-0980 was tested in ER+ (MCF7, BT-483, T-47D and MDA-MB-415), trastuzumab-sensitive HER2+ (BT-474, SK-BR-3), trastuzumab-resistant (BT-474/HerR), and PIK3CA mutated/HER2+ (HCC1954 and MDA-MB-453) breast cancer cells. We have examed the effects of GDC-0980 on the (a) cell survival/proliferation, (b) downstream signaling pathways for proliferation and apoptosis and (c) 3D ON-TOP-colony formation. Results: Treatment of ER+ and HER2+ cell lines with GDC-0980 in vitro showed that 1) cell lines were sensitive to single agent GDC-0980 with 50% inhibitory concentration ranging from 50 nM - 150 nM in ER+ cell lines and 100 nM - 700 nM in HER2+ cell lines 2) 70-80% anti-proliferative activities were observed on 3D-ON TOP colony formation assay in both ER+ and HER2+ cells 3) GDC-0980 dose- and time-dependently blocked downstream effectors of the PI3K-AKT-mTORC1/C2 pathways i.e. p-AKT (Ser 473, The 308), p-p70S6K, p-S6 ribosomal protein, p-4E-BP1 (only at higher concentration) 4) phosphorylation of ERK was downregulated in ER+/PIK3CA helical domain mutated cells (MCF7) but it was upregulated in ER+/PTEN mutated (loss-of-function) cells (MDA-MB-415) 5) interestingly upstream HER3 was upregulated following the treatment of GDC-0980 and 6) both ER+ and HER2+ cell lines exhibited an increase in annexin V positivity following GDC-0980 treatment. Conclusion: Our preclinical in vitro data demonstrate that concurrent inhibition of PI3K and mTORC1/C2 is likely to be more effective in both ER+ and HER2+ breast cancer cells than the inhibition of mTORC1 alone. We are currently studying the effect of GDC-0980 on cell cycle analysis in ER+ and HER2+ cell lines, the results of which will be presented in the meeting. Citation Format: Yuliang Sun, Pradip De, Jennifer H. Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones. In vitro potency of dual PI3K/mTORC1/C2 inhibitor, GDC-0980 in ER+ and HER2 overexpressing breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4717. doi:10.1158/1538-7445.AM2015-4717