Abstract 5121: A targeted approach to identify activators of class IA phosphoinositide-3-kinase in cancers using tandem mass spectrometry

Abstract

Abstract A majority of human cancers exhibit aberrant activation of the phosphoinositide 3-Kinase (PI3K) pathway. In many cases this activation is due to mutations or amplifications in upstream activators of PI3K resulting in activation by direct binding of phosphotyrosine proteins (e.g., receptor tyrosine kinases (RTK) or adaptors such as IRS-1/2 or Gab1/2) to the p85 regulatory subunit of PI3K. To date, experiments to identify the mechanisms of PI3K activation in cancer have remained difficult and cumbersome. Since inhibitors of many of these RTKs are either already approved or in clinical trials, identification of the major upstream activators of PI3K in a given tumor could suggest the appropriate therapeutic intervention. Here we present a quantitative mass spectrometry approach (targeted ion MS/MS – TIMM) for identifying the upstream activators of PI3K in cancer cell lines grown on plastic as well as in tumor Xenografts. Importantly, we show that in a series of non small cell lung carcinoma cell lines, it is possible to predict the appropriate drug for treating the cells based on the upstream activator of PI3K as revealed by TIMM. Specifically, we identified how PI3K is activated in MET amplified, EGFR and EML4-ALK driven non-small cell lung cancers (NSCLCs) both in vitro and in vivo, and were successful in identifying the optimal RTK inhibitor treatment for the H1703 NSCLC cell line. Additionally, this technology revealed that TORC1 inhibition leads to activation of PI3K via IRS-2, not IRS-1 in KRAS mutant cell lines. 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 5121. doi:10.1158/1538-7445.AM2011-5121