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Table 1 Single-node resistance mechanisms to PI3K inhibitors ordered by their effect on Apoptosis

From: A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

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
  1. 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