Abstract 3590: Profiles of contributing genes to sensitive/resistant phenotypes of 11 different oncology therapeutic agents across 240 cell lines
Authors: O'Day Christine L. , Ovechkina Yulia , Marcoe Karen , Keyser Robert , Yoshino Karen , Nguyen Phuong , Bernards Karen , Shively Rodney , Hnilo James , Mulligan Jenny , Lin Teddy , Wang Shimin 
Published: February 2011

As more kinase inhibitors and other less cytotoxic drugs have entered the oncology market, it is imperative for clinical success to identify subsets of the population that would have increased sensitivity or resistance to given agents. To this end, we have cultured 240 cell lines with defined genetic analysis to correlate sensitive and resistant cell lines. To test this hypothesis, we have screened 11 clinical and pre-clinical oncology agents to identify sensitive and resistant genes in each drug class. The list of oncology agents tested included inhibitors of mTorr, ABL, MEK, PDGF, VEGF, FLT3, Aurora kinases, HSP90, EGFR, Topo II and microtubule disassembly. Three of the drugs are multikinase inhibitors. Compounds were run in a multiplexed assay using a 10 pt dose response spanning five logs of sample concentration and evaluated for antiproliferative effects, ability to induce apoptosis and the ability to enhance or decrease cells in G2M. Once analyzed, cell lines were separated into sensitive, resistant and intermediate in their activity towards the agent. Sensitive and resistant cells were further profiled against, mutation, expression and SNP data to identify genes involved in the sensitive/resistant phenotype. As expected, the most sensitive cell lines against a clinical ABL inhibitor were the CML derived cell lines. The multikinase inhibitors, primarily directed at VEGF/PDGF angiogenic pathways not detectable in this monolayer cell proliferation assay, were found to be sensitive against a common subset of cell lines. Genetic tendencies common between these cell lines are being investigated. In addition, a MEK inhibitor, though failed in the clinic as a general oncology agent, was selective against BRAF mutations presenting in many melanomas. Currently, several new MEK inhibitors are being tested in the clinic for melanomas. All of the 30 most sensitive cell lines against the MEK inhibitor had either a BRAF or a RAS mutation. The sensitivity was also exclusive of retinoblastoma (RB) mutations. In the 30 most sensitive cell lines, 50% had BRAF mutations and 0% had RB mutations. In the 30 most resistant cell lines, 0% had BRAF mutation and 25% had RB mutations. In fact, 10 of the 11 known RB mutations were present in the 50 most resistant cell lines. Moreover, it is known that cyclin D overexpression confers resistance and since RB is a substrate of cyclin D, it follows that RB mutations may also confer resistance to MEK inhibitors. Further analysis may provide a complete picture of sensitivity and resistance to MEK inhibition and give insight for design of promising combination therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3590.