Abstract
Abstract Background: HER2 amplification/overexpression frequently co-occurs with PI3K pathway activation in breast tumors. Mutations in PIK3CA are known to be involved in a wide range of human cancers including HER2+ breast cancer, and mutant PIK3CA is thought to act as an oncogene. Here, we evaluate the efficacy of GDC0032, a p110 beta-sparing PI3K inhibitor against HER2+ or HER2+/PIK3CA mutated breast cancer cells. MATERIALS AND METHODS: Four HER2+ breast cancer (BC) cell lines consisting of three activating (either helical or kinase domain) PIK3CA mutation (HER2+/ER+ and HER2+/ER-) were analyzed for proliferation, apoptosis, cell cycle and signaling pathway activation assays. Preclinical efficacy of GDC-0032 was also evaluated in vivo in a mouse model. RESULTS: 1) All HER2+ and HER2+/PIK3CA mutant cell lines exhibited low IC50 values (ranging from 0.1 µM-1.5 µM) irrespective of ER-positive or not. 2) GDC-0032 caused a strong differential growth inhibition in both HER2+ and HER2+/ /PIK3CA mutated breast cancer cell lines when compared to lines that were HER2- and PIK3CA wild type by 3D-ON-TOP clonogenic assay. 3) Administration of GDC-0032 induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependent manner. Furthermore, induction of apoptosis was more with GDC-0032 when combined with RAD001. 4) GDC0032 also blocked expression of CYCLIN D1. 5) Investigation of the signal transduction revealed that the treatment of GDC-0032 reduced the level of p-AKT (Ser473 and Thr308), and p-S6 expression is indicating the down-regulation of downstream signaling of PI3K and mTOR pathway. 6) GDC-0032 was highly active at reducing established tumor growth in vivo in BC mouse xenografts harboring PIK3CA mutation and HER2 amplification. CONCLUSION: Our in vitro or in vivo data showed that GDC-0032 was highly efficient either as a single agent as well as with RAD001 in HER2+/PIK3CA mutated breast cancer cell lines. Our data suggest that GDC-0032 represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification in breast cancer. Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Casey Williams, Nandini Dey, Brian Leyland-Jones. GDC-0032, a p110 beta sparing PI3K inhibitor is highly efficient on PIK3CA-mutated and HER2-amplified breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1348. doi:10.1158/1538-7445.AM2017-1348
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