Table 1.
Single-node resistance mechanisms to PI3K inhibitors ordered by their effect on Apoptosis
| Perturbation | Apoptosisnorm | Proliferationnorm | Mechanism |
|---|---|---|---|
| PI3K = 1,2; PIP3 = 1,2 | 0.00 | 0.50 | PI3K |
| AKT = 1 | 0.00 | 0.50 | AKT |
| HER2/HER3 = 2 | 0.00 | 0.50 | RTK |
| PIM = 1 | 0.00 | 0.50 | AKT |
| MAPK = 1 | 0.25 | 0.25 | MAPK |
| MAPK = 2 | 0.00 | 0.25 | MAPK |
| BIM = 0 | 0.25 | 0.25 | Apoptosis |
| BAD = 0 | 0.25 | 0.25 | Apoptosis |
| SGK1 = 1 | 0.25 | 0.25 | AKT |
| FOXO3 = 0, FOXO3_Ub = 1 | 0.33 | 0.13 | AKT |
| mTORC1 = 1 | 0.38 | 0.50 | mTORC1 |
| translation = 1 | 0.38 | 0.50 | mTORC1 |
| TSC = 0 | 0.38 | 0.50 | mTORC1 |
| PRAS40 = 0 | 0.38 | 0.50 | mTORC1 |
| MCL1 = 1 | 0.38 | 0.25 | Apoptosis |
| BCL2 = 1 | 0.50 | 0.25 | Apoptosis |
| pRb = 3 | 0.70 | 0.50 | Proliferation |
| E2F = 3 | 0.70 | 0.50 | Proliferation |
| cycE_CDK2 = 1 | 0.70 | 0.50 | Proliferation |
| p21_p27 = 0 | 0.70 | 0.49 | Proliferation |
The sustained state indicated in the first column yields a decrease in Apoptosisnorm from 0.7 and/or an increase in Proliferationnorm from 0.25, which are the activities of these nodes with only PI3K inhibition. Certain node perturbations that are equivalent in the network sense and lead to the same effect are grouped; specifically, PIP3 = 1 or 2 with PI3K = 1 or 2; FOXO3_Ub = ON with FOXO3 = OFF