Abstract
Abstract The class I phosphatidylinositol 3’ kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting the PI3K pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. GDC-0941 is a pan-inhibitor of all 4 isoforms of class 1 PI3K that is currently undergoing testing in the clinic. We were interested in the predictive value of candidate biomarkers in NSCLC to help inform clinical trial biomarker strategies in this indication. We assembled a focused panel of cell lines with key alterations in the PI3K pathway isolated from other genetic events to the extent possible. The approach involved pharmacogenomic and proteomic profiling. We found that models harboring key pathway alterations were exquisitely sensitive to GDC-0941. In particular, cell lines with EGFR mutations, PIK3CA mutations or amplification were the most sensitive. Inhibition of PI3K in mechanism of action studies showed effects consistent with induction of apoptosis, cell cycle arrest, and impairment of translation in models with these key alterations. In addition, gene expression changes of genes downstream of PI3K were seen upon treatment with GDC-0941 in sensitive cell lines but not those that were resistant. We extended these studies to NSCLC tumor samples and evaluated the prevalence of important pathway alterations, including PTEN loss, PIK3CA amplification, LKB1 loss in tumors representing distinct histopathological subtypes. We find that certain candidate biomarkers show subtype specific associations, and will discuss the implications for the development of PI3K-targeting agents in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4116. doi:10.1158/1538-7445.AM2011-4116
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