Fig. 6

Meta-network illustrating synergistic interventions and resistance mechanisms to PI3K inhibitors. The colored rectangles correspond to the pathways introduced in Fig. 3, and the edges between them represent aggregated regulatory relationships between pathways. In these relationships, and also when referring to a pathway as active or inactive, we focus on the index (named) member of the pathway. Thus, when saying that the mTORC1 pathway is active we mean that mTORC1, EIF4F and S6K are active, TSC and PRAS40 are inactive. Thick continuous lines indicate active pathways/interactions, thick and dashed lines represent partially active pathways/interactions, thin and dashed lines mean inactive pathways/interactions. For the node names indicated inside the colored rectangles, blue indicates inhibition/inactivity and red indicates increased activity. a Signaling pathway activity in response to PI3K inhibition. ER signaling is still active (partly due to the release of its inhibition by AKT), while the apoptosis and proliferation pathways are partially active. Inhibition of the nodes indicated in blue font or constitutive activity of Rb is predicted to have a synergistic effect with PI3K inhibition. b Resistance mechanisms to PI3K inhibitors. Sustained activity of the nodes indicated with red font inside each pathway can (at least partially) restore the pathway’s activation and obstruct the effectiveness of PI3K inhibition. Sustained inactivity of the nodes indicated with blue font can have a similar effect. For simplicity, the HER2/HER3 resistance mechanism is not included in a separate RTK module but as part of the pathways activated by HER2/HER3, namely MAPK and PI3K