Abstract
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway is a common phenomenon in cancer due to multiple mechanisms, including mutation of PI3KCA, loss or mutation of PTEN, or over-expression of receptor tyrosine kinases. We recently developed a novel AKT kinase inhibitor, AZD5363. To explore the activity of AZD5363 and elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer, we investigated the effects of pharmacological inhibition of AKT on a panel of 20 gastric cancer cell lines. We demonstrated that gastric cancer cells with PIK3CA mutations were selectively sensitive to AZD5363. Interestingly, we found that HGC27, a cell line harboring both PI3KCA mutation and PTEN loss, displayed the greatest sensitivity to this AKT inhibitor, suggesting possible synergy between these two genetic alterations. To further dissect the role of PI3KCA mutation and PTEN loss in response to AKT inhibition, we tested, using in vivo xenografts, the antitumor activity of AZD5363 in HGC27 and two other primary gastric cancer models containing either PI3KCA mutation or PTEN loss. Our data indicated that AZD5363 monotherapy treatment led to complete tumor regression in the HGC27 xenograft model, correlating with the induction of cell apoptosis and inhibition of PI3K/AKT pathway. On the other hand, the same treatment evoked only a moderate response (∼60% TGI) in the PI3KCA mutant primary xenograft model. Whilst monotherapy AZD5363 or docetaxel were not active in the PTEN negative, PIK3CA wild-type primary xenograft model, significant anti-tumor activity was seen when AZD5363 was combined with docetaxel. These results suggest that PI3KCA mutation is an important determinant of response to AKT inhibition in gastric cancer. Moreover, combination with AZD5363 can overcome innate resistance to docetaxel in a gastric cancer explant model. 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 3200. doi:1538-7445.AM2012-3200
Published Version
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