Abstract 5220: Identifying AML-specific key targeted drugs using high-throughput drug sensitivity and resistance testing profiles of AML cells.

Abstract

Abstract Introduction: Conventional cytotoxic chemotherapy regimens for adult acute myeloid leukemia (AML) are effective in curing less than 50% of the patients, and there is a major need for targeted drugs with better anti-cancer selectivity. Here, our aim was to i) identify potential clinically used or emerging cancer drugs by quantitative drug sensitivity and resistance testing (DSRT) of 16 AML cell lines ii) compare the cell line data with results obtained from tested 24 ex vivo AML patient specimens iii) identify genomic correlations potentially explaining drug responsiveness. Methods: The cancer pharmacopeia-wide drug collection is composed of 119 FDA approved and 90 investigational chemical compounds including cytotoxic agents and cell signaling molecule inhibitors. Each drug was tested over a 10,000-fold concentration range and that has generated quantitative five point dose-response curves. AML cells were plated in 384 well plates (where the drugs were pre-printed using an acoustic nano-dispensing technology, Labcyte®) and incubated in standard cell culture conditions. Cell viability was measured by Cell Titer Glow® luminescence assays. Analysis of dose response curves using Dotmatics® software resulted in IC50 values. Moreover, the genomic profiles of the AML cell lines were determined by microarrays and/or next-gen sequencing data for further integration with drug responses. Results: Comprehensive data analysis of 16 AML cell lines indicated that specific targeted drugs were selectively killing AML cells. The data analysis revealed relatively strong responses for MEK inhibitors in most AML cell lines (e.g. refametinib 87%, trametinib 82%, selumetinib 75%) while 21% of ex vivo AML patient samples were sensitive to these MEK inhibitors. In case of rapalog sensitivity, 80% of AML cell lines (e.g. temsirolimus 82%, everolimus 71%, sirolimus 81%) and 25% of ex vivo AML patient cases were responsive to the mTOR inhibitors. The AML cell lines carrying FLT3-ITD mutations were extremely sensitive to FLT3 inhibitors (e.g. quizartinib, lestaurtinib, tandutinib, and sorafenib) but very few responses to FLT3 inhibitors were observed in AML patients carrying an ITD mutation in the FLT3 kinase. Summary: Systematic DSRT profiling of AML cell lines illustrates drug sensitivity patterns to classify the cell lines as sensitive or resistant to specific classes of drugs. mTOR and MEK inhibitors were among the most effective inhibitors for most cell lines and also in some ex vivo patient cases suggesting that these drugs may have potential as therapeutic agents in AML. Also, bioinformatics predictions can be used to identify key synergistic combinations of tested drugs for effective AML therapy. Further integration of molecular profiles and functional responses of AML cell lines will help provide better understanding of drug efficacy based on known genetic background of the disease. Citation Format: Disha Malani, Astrid Murumägi, Tea Pemovska, Bhagwan Yadav, Evgeny Kulesskiy, Jing Tang, John Patrick Mpindi, Maija Wolf, Riikka Karjalainen, Tero Aittokallio, Caroline Heckman, Kimmo Porkka, Krister Wennerberg, Olli Kallioniemi. Identifying AML-specific key targeted drugs using high-throughput drug sensitivity and resistance testing profiles of AML cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5220. doi:10.1158/1538-7445.AM2013-5220