Network quantification of EGFR signaling unveils potential for targeted combination therapy

Analysis of the signaling response of colon cancer cells to systematic perturbations reveals an EGF receptor-mediated cross-talk between the MAPK and AKT pathways. Accordingly, the predicted combinatorial treatment is shown to inhibit tumor growth in vivo.
A modular response analysis model trained on perturbation data in a panel of colon cancer cells revealed a negative feedback from MAPK signaling to the EGF receptor, which leads to AKT cross-activation after MEK inhibition. The model predicted that successful inhibition of growth-factor signaling in colon cancer requires combined inhibition of MEK and EGF receptor to prevent AKT activation and tumor cell survival, which was confirmed by growth assays. A xenograft tumor model of KRAS-mutant colon cancer showed that EGFR receptor inhibition alone has no effect, but in combination with a MEK inhibitor successfully reduces tumor growth.
The epidermal growth factor receptor (EGFR) signaling network is activated in most solid tumors, and small-molecule drugs targeting this network are increasingly available. However, often only specific combinations of inhibitors are effective. Therefore, the prediction of potent combinatorial treatments is a major challenge in targeted cancer therapy. In this study, we demonstrate how a model-based evaluation of signaling data can assist in finding the most suitable treatment combination. We generated a perturbation data set by monitoring the response of RAS/PI3K signaling to combined stimulations and inhibitions in a panel of colorectal cancer cell lines, which we analyzed using mathematical models. We detected that a negative feedback involving EGFR mediates strong cross talk from ERK to AKT. Consequently, when inhibiting MAPK, AKT activity is increased in an EGFR-dependent manner. Using the model, we predict that in contrast to single inhibition, combined inactivation of MEK and EGFR could inactivate both endpoints of RAS, ERK and AKT. We further could demonstrate that this combination blocked cell growth in BRAF- as well as KRAS-mutated tumor cells, which we confirmed using a xenograft model.