Abstract LB-330: Systematic understanding of tyrosine kinase activation pattern in human cancers
Authors: Du Jinyan , He Frank , Julian Bina , Mani DR , Kung Andrew , Golub Todd 
Published: July 2012

Tyrosine kinases (TKs) are frequently, aberrantly activated in human cancers. Moreover, they could be easily inhibited by small molecules and thereby represent excellent therapeutic targets. Here, to understand the role of TK signaling in cancer development and maintenance, and to identify novel TK inhibitor based therapeutic strategies, we have systematically profiled the tyrosine kinase activation events in human cancers. In our previously published study, we have developed a high-throughput, multiplex antibody-based assay capable of identifying activated TKs regardless of their mode of activation. Through an initial profiling effort on a panel of 130 cell lines, we found frequent SRC activation in glioblastomas in the absence of genomic alterations. Currently, the expanded technology is capable of profiling 82 out of the 90 TKs, adaptors and other important signaling molecules. In addition, we have developed assays to measure the activity of PI3K, ERK and NOTCH pathways. With this technology, we have profiled over 1,400 cell lines and primary tumors to learn the TK activation pattern in various types of cancers. From the current TK activation map, we observed that a few tyrosine kinases are frequently activated in various human cancers while most are phosphorylated at low frequencies. Certain types of cancers exhibit cancer-type specific TK activation signatures. Interestingly, some patterns of TK activation are common among multiple tumor types. Together, these observations support the importance of personalized treatment (i.e. choosing kinase inhibitors based on TK activation profile of a tumor). Through this profiling effort, we have identified TKs that are hyperphosphorylated in a subset of the samples. Small molecule inhibitor targeting these TKs produced temporary inhibition on tumor growth both in vitro and in vivo. Next, we will initiate synthetic lethal RNAi screens in order to identify potentially effective combinations which could help overcome the acquired resistance. In parallel, we are in the process of applying this technology to systematically characterize the effects of various perturbations on TK signaling, including but not limited to RNAi knockdowns, cDNA overexpresssions, compound inhibitions and growth factor stimulations. We have also adapted this method to quantify protein-TK interactions and have produced a preliminary kinase-TK interaction map. By integrating these datasets (i.e. baseline profiles, perturbation characterizations and kinase-TK interactions), we have gained a comprehensive understanding on TK activation pattern in human cancers. Beyond the mechanistic understanding of tyrosine kinase signaling, our study has identified potential targets for devising effective therapeutic strategies for treating cancer patients.

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 LB-330. doi:10.1158/1538-7445.AM2011-LB-330