Faratian et al., (2009). Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab.
August 2012, model of the month by Stuart Moodie
Original model: BIOMD0000000424
Resistance to anti-cancer drug therapies is a significant problem in oncology. The problem is akin to antibiotic resistance in bacteria, where the target cells develop resistance typically by genetic mutation. The subject of this study by Faratian et al. [1, BIOMD0000000424], is the drug trastuzumab that targets the HER2 (aka ErbB2) receptor and is used as a treatment for breast and ovarian cancers. The benefits of trastuzumab are marginal, increasing overall survival by 1 percentage points (from 95%) after 1 year. The assumption is that this low rate of benefit is due to drug resistance. By selecting patients not resistant to trastuzumab resistance, one will avoid both the waste of an expensive, but ineffective treatment; and the personal cost of a patient undergoing chemotherapy with unpleasant and toxic side-effects for little clinical benefit. Better targeting of trastuzumab therapy is clearly important and this study endeavours to use a kinetic model to investigate the role of the phosphatase PTEN as a potential biomarker for trastuzumab resistance in Ovarian cancer.
The model describes the downstream signalling response of Akt and ERK to Heregulin (HRG) stimulus of the ErbB3 and Erb2 receptors (Figure 1). HRG binds to Erb3, which promotes heterodimerisation with HER2 (ErbB2), thus activating PI3K and Ras. Activated Ras (Ras-GTP) activates Raf which phosphorylates MEK in the familiar MAPK cascade that results in the activation of ERK (ppERK). Activated PI3K is localised to the surface of the cell membrane where it can phosphorylate the phospholipid phosphatidylinositol (PI) into phosphatidylinositol-3-phosphate (PIP3). Akt binds to PIP3 thus recruiting it to the cell membrane where it is phosphorylated by the membrane associated kinase PDK to form ppAkt. Both these endpoints play important roles in regulating functions related to the cell cycle - hence their importance in cancer.
Figure 2 Catalytic cycle of PTEN with lipid phosphatase activity and it's autodephosphorylation activity. (figure taken from supplementary material of ).
The model was derived from the Hatakeyama et al. [2, BIOMD0000000146] describing Erb4 signalling and the Kholodenko's seminal model of the MAPK cascade [3, BIOMD0000000048], but has 2 interesting and novel features. First it incorporates a detailed mechanism of PTEN regulation (Figure 2) in which the inactive phosphorylated form is activated by an auto-dephosphorylation step. PTEN's protein phosphatase activity has been proposed to enable PTEN to dephosphorylate itself, but at the time of the paper's publication the evidence was thin, although a recent paper  seems to justify this assumption. The significant difference in protein stability between pPTEN (half-life ~2hrs) and PTEN (half-life ~45mins)  was not included in the model. The second detailed mechanism was a 2 stage mechanism (see Figure 3) to describe ligand-receptor binding and heterodimerisation of ErbB2/ErbB3. This improved correspondence with experimental data when modelling ErbB2 inhibition with pertuzumab. The model parameters were fitted to experimental data obtained from the PE04 ovarian cell line after HRG and HRG and pertuzumab exposures, respectively. Subsequent model predictions used this model.
The model was used to examine the importance of PTEN activity in pertuzumab resistance and because PTEN is involved in a regulatory cycle with PI3K, the study focused on how changes to the relative activity of these affected resistance. To do this a integrative parameter γ was created which was described the balance of PTEN and PI3K activities. With a low γ, the system amplifies small receptor signals and at high γ, the system exhibits pertuzumab resistance. These theoretical observations were verified experimentally by treating PE04 cells with a PTEN inhibitor and a PI3K inhibitor. Further examination of other cell lines in vitro and from primary breast cancer tumor samples in the clinic suggest that the PTEN/PI3K balance described in the model is an important indicator of pertuzumab resistance.
This model was used in a study that demonstrates the utility of a model in asking hypothetical questions that can guide experimental investigation. In this case the authors of the study were able to suggest that a quarter of ErbB2 over-expressing cancer patents may be spared ineffective treatment if PTEN levels were used to determine suitability for pertuzumab treatment. In addition, they could suggest that a combination therapy of pertuzumab and a PI3K inhibiting drug could be an effective treatment in low PTEN expressing tumors.
Figure 1 Networt schema of MAPK and PI3K signalling. (figure taken from ).
Figure 3 Detailed scheme of heterodimerisation of HER3 (E3) and HER2 (E2) receptors along with formation of the transphosphorylated complex, pE23H. (figure taken from the supplementary material of ).
- Faratian et al. Systems biology reveals new strategies fro personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Res. 2009; Aug ;69(16):6713 [PMID:19638581]
- Hatakeyama et al. A computational model of the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. Biochem J. 2003; Jul ;373(Pt 2):451 [PMID:12691603]
- Kholodenko et al. Quantification of short term signaling by the epidermal growth factor receptor. J Biol Chem. 1999; Oct ;274(42):30169 [PMID:10514507]
- Tibarewal et al. PTEN protein phosphatase actvity correlates with control of gene expression and invasion, a tumor-suppressing phenotype, but not with AKT activity. Sci Signal. 2012; Feb 28 ;5(213):ra18 [PMID:22375056]
- Birle et al. Negative feedback regulation of the tumor suppressor PTEN by phosphoinositide-induced serine phosphorylation. J Immunol. 2002; Jul 1 ;169(1):286 [PMID:12077256]