Abstract 2227: P110 α-specific inhibitor is more suitable in PIK3CA mutated breast cancer model but ineffective in PTEN loss of function breast cancer model
Authors: Sun Yuliang , Dey Pranammya , Wu Hui , Leyland-Jones Brian 
Published: August 2012

Abstract
Background: Members of the phosphatidylinositiol 3-kinase (PI3K) pathway are frequently upregulated/amplified in broad range of cancers including breast cancer. The PIK3CA mutation or the loss-of-function of PTEN, which are found in different subsets of breast cancer, activates the PI3K-AKT-mTOR pathway, resulting in breast cancer development, progression and lower clinical benefit rate. Purpose: We investigated the comparison of inhibitory potency of p110α-specific inhibitor (INK1402) versus PI3K/mTOR dual inhibitor (BEZ235) in PI3K activated (define as activating mutation of PIK3CA or by loss-of-function of PTEN) hormone receptor positive (HR+) and triple negative (TN) breast tumor cells (a proof-of-concept study). Experimental Design: We used HR+ (MCF7, T47D and MDA-MB415) and TN (MDA-MB231 and MDA-MB468) breast cancer cell lines. We have tested the effects of INK1402 and BEZ235 on the, (a) cell survival/proliferation, (b) downstream signaling pathways for proliferation and (c) 3D ON-TOP-colony formation. Results: Here, we demonstrate that 1) both PIK3CA mutated and PTEN null or mutated breast cancer cells (ER+ and TN) are sensitive to BEZ235 (∼IC50 7 nM-30 nM), 2) only PIK3CA mutated cells (not PTEN loss-of-function cell lines) are sensitive to INK1402 (∼IC50 2 µM-12 µM), 3) anti-clonogenic growth property (3D-ON TOP colony formation assay) of INK1402 is more pronounced (80%-100%) in PIK3CA mutated cells as compared to PTEN loss-of-function cells (∼50%-60%), 4) BEZ235 shows anti-clonogenic property (3D-ON TOP colony formation assay) in all cell lines (∼60%-80%), 5) INK1402 and BEZ235 differentially inhibit PI3K-AKT-mTOR pathway and RAS-MAPK pathway in PIK3CA mutated, PTEN mutated (ER+), and PTEN null (TN) breast cancer cell lines: a) INK1402 is significantly more effective in PIK3CA mutated cell lines as compared to PTEN null or mutated cell lines, b) BEZ235 blocks the activation of PI3K-mTOR pathway components (p-AKT, p-S6RP) in both PIK3CA mutated and PTEN null or mutated cell lines, and c) interestingly, INK1402 blocks ERK activation in PIK3CA mutated cells whereas BEZ235 upregulates ERK activation in both PI3K mutated and PTEN null or mutated cell lines. Conclusion: These findings confirm the mutually exclusive behavior of PIK3CA mutation and PTEN loss in breast tumor models (Ellis MJ et al Cancer Research 2009; Russillo M et al JCO 2011). Our initial finding may provide a rationale to guide selection of patients who may benefit from PI3K-isoform (p110α)-specific inhibitor or PI3K/mTOR dual inhibitor therapy, and highlights the importance of accurately accessing the expression/functional status of PIK3CA or PTEN status in breast tumor samples. Acknowledgement: We sincerely thank to Novartis and Intellikine Inc for proving us with BEZ235 and INK1402 respectively.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2227. doi:1538-7445.AM2012-2227