Our GSA procedure indicated PDK1 and PI3K as promising targets to suppress Akt phosphorylation, suggesting that the efficient suppression of pAkt signal can be achieved both with single drugs (a PDK1 or a PI3K inhibitor), and with combinations of each of these compounds with anti-ErbB2 inhibitor pertuzumab. Our experiments confirmed that both the PDK1 inhibitor UCN-01, and the PI3K inhibitor LY294002, effectively inhibited pAkt signalling in two different ovarian carcinoma cell lines, when used as single drugs and in combination with pertuzumab. Our findings Nintedanib datasheet with regard to potential biomarkers of pertuzumab
resistance (PTEN, PP2A, PI3K) were in agreement with our own data (Faratian et al., 2009b and Goltsov et al., 2011) and other existing studies. Importantly, many of the targets selleckchem and biomarkers identified by our GSA procedure have been previously highlighted in other experimental and modelling
studies, that can be considered as a confirmation of the predictive capabilities of the method. Since LSA method still remains the most popular way for deriving quantitative predictions from ODE-based models, in this contribution we focussed on the discussion of our GSA procedure in comparison with this popular technique. We argue that GSA can substantially add value to the analysis of cancer-related network models, since, in contrast to LSA, it can successfully deal with the poor identifiability and uncertainty tuclazepam of the parameters associated with such models. The comparison of the GSA and LSA predictions, generated for our reference ErbB2/3 network system, revealed that control parameters, highlighted by LSA represented a subset of GSA-derived predictions; importantly, these two methods assigned significantly different ranks to some of the key network parameters (e.g. ErbB3, PDK1, PP2A). We suggest that the observed discrepancy in LSA and GSA predictions may originate
from substantial differences in theoretical assumptions and technical implementation of these methods, that define their range of applicability. LSA may be suitable to identify critical network components within particular cell type, used for initial model calibration, whereas GSA can help to explore a wider range of possible targets, which are likely to be valid for the majority (but not all) possible network implementations. Though we have illustrated our GSA procedure on a single relatively well known system of ErbB associated signalling, we suggest that the proposed method may have broader applicability, since the general pipeline of our procedure is based on well-established and tested statistical and computational techniques. However, for the method to produce meaningful results, the input network model should satisfy certain criteria.