Figure 5. Combined mTORC1/2 and MEK inhibition is an effective therapeutic approach in RICTOR/KRAS-altered settings and results in synergistic anti-tumor effects.
(A) Five NSCLC cell lines (3 RICTOR amplified (red), 2 RICTOR non-amplified (blue) and two immortalized human bronchial epithelial cell lines (HBECs, black) were treated with DMSO (control), selumetinib (1 μM), AZD2014 (0.1 μM), or the combination selumetinib (1 μM) with AZD2014 (0.1 μM). Mutation status of KRAS, LKB1, PTEN, and EGFR are shown below each cell line. After 72 hours of treatment, cell viability was compared to control DMSO treated cells and measured by MTT assay. Data are graphed as the mean percentage ± percent SD. **P < 0.01; ***P < 0.0001. (B) NSCLC cells were incubated with increasing concentrations of AZD2014 (0.024–12.5 μM) and a fixed dose of selumetinib (0, 2.3, 4.6, 9.3, or 18.7 μM) for 96 hours. Controls were treated with DMSO only. Cell viability was analyzed by MTS assay. Data are graphed as the mean percentage ± percent SD. Combination index (CI) values were calculated using ComboSyn software (ComboSyn Inc, Paramus, NJ). The CI parameters used were: CI = 0–0.9, synergism; CI = 0.9–1.1, additive effect; CI > 1.1, antagonism.