Abstract B28: Identification of drug-response biomarkers for combined mTORC1/2 and MEK1/2 investigational agents using a large-scale cancer cell line screen

Combination therapy in oncology drug development has the potential to overcome resistance against single agent-based therapy. In many cancers, the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways confer major cell growth and survival mechanisms. Therefore, a greater treatment effect may be achieved by inhibiting both pathways simultaneously through drug combination. In this study, the enhanced anti-proliferative activity of investigational drug MLN0128 (mTORC1/2 investigational agent) when combined with TAK733 (MEK1/2 investigational agent) was assessed using an in-vitro cell viability assay on 240 cancer cell lines. Cells were administered with MLN0128 and TAK-733 in DMSO in ten 2-fold serial dilutions and cell viability was measured using Promega's CellTiter-GLO® assay after a 72 hour incubation period. The data points were fit to a 9-parameter model to obtain a response surface and the effect of the combined administration for each cell line was measured using a non-linear blending score estimated from the response surface. Statistical analysis was conducted to determine if the estimated combination effect was associated with known mutated oncogenes, tumor suppressor genes, or cancer histology reports of the 240 cell lines. Interestingly, the synergy of combined agents appeared to be mainly driven by TAK733, as cell lines sensitive to TAK733 as a single agent demonstrated beneficial combination effect with the addition of MLN0128. Furthermore, cell lines with mutations in KRAS, NRAS, and BRAF showed greater synergy scores of the combination. Likewise, cell lines of colon, pancreatic, and skin origins were more sensitive to the combination. Of particular interest are cell lines with mutated KRAS/NRAS or colon origins since they were generally resistant to single agent MLN0128, but became sensitized to the combination with TAK733. In conclusion, our study of drug combination assays on a large-scale in-vitro cell line panel revealed that mutant KRAS/NRAS or colorectal cancers may be sensitive to combined MLN0128 with TAK733. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B28. Citation Format: Hyunjin Shin, Derek Blair, Bin Li, Greg Hather, William L. Trepicchio, Jeffrey Ecsedy, Esha Gangolli. Identification of drug-response biomarkers for combined mTORC1/2 and MEK1/2 investigational agents using a large-scale cancer cell line screen. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B28.