SSI: A Statistical Sensitivity Index for Chemical Reaction Networks in cancer

Abstract

At the cellular level, cancer is triggered by mutations of the proteins involved in signalling networks made of hundreds of reacting species. The corresponding mathematical model consists of a large system of non-linear Ordinary Differential Equations for the unknown proteins concentrations depending on a consistently large number of kinetic parameters and initial concentrations. For this model, the present paper considers the problem of assessing the impact of each parameter and initial concentration on the system's output. More specifically, we introduced a statistical sensitivity index whose values can be easily computed by means of principal component analysis, and which leads to the partition of the parameters' and initial concentrations' sets into sensible and non-sensible families. This approach allows the identification of those kinetic parameters and initial concentrations that mostly impact the mutation-driven modification of the proteomic profile at equilibrium, and of those pathways in the network that are mostly affected by the presence of mutations in the cancer cell.

In-silico modelling of the mitogen-activated protein kinase (MAPK) pathway in colorectal cancer: mutations and targeted therapy

“…Sensitivity analysis is the technical tool that allows the quantitative assessment of the impact of the kinetic parameters' uncertainty on the CRN equilibrium state. In its local version, sensitivity analysis is an indicator of the impact that a specific mutation has on the expression of the corresponding protein, and, even more importantly, it is able to identify the sub-networks that are mostly affected by the mutation (Biddau et al, 2023).…”

“…More importantly, local and global effects induced on the network by LoF and GoF mutations can be quantified by computing the relative difference between the protein concentrations at the equilibrium point of the original CR-CRN and that at the equilibrium of the network obtained by applying the proper projection operator(s) (Sommariva et al, 2021a). Additionally, analysis of the sensitivity of protein concentrations at equilibrium with respect to the values of the kinetic parameters of the dynamical model may help in identifying the specific reaction or subnetwork mostly affected by each genetic alteration (Biddau et al, 2023).…”

“…The proposed model has been used to simulate the functional alterations induced on the CR-CRN by some of the mutations more commonly found in CRC, including the GoF of genes PI3K, KRAS, and BRAF, and the LoF of genes PTEN, AKT, and TGFβRII (Sommariva et al, 2021a;Sommariva et al, 2021b;Biddau et al, 2023), and a first attempt in modelling the action of Dabrafenib, a drug targeting BRAF, has been performed by Sommariva et al (2021b). The obtained results have been extensively compared with results previously published in literature.…”

In-silico modelling of the mitogen-activated kinase (MAPK) pathway in colorectal cancer: mutations and targeted therapy

“…The proposed model has been used to simulate the functional alterations induced on the CR-CRN by some of the mutations more commonly found in CRC, including the GoF of PI3K, KRAS, and BRAF, and the LoF of PTEN, AKT, and TGFβRII (Sommariva et al, 2021a,b;Biddau et al, 2023), and a first attempt in modelling the action of Dabrafenib, a drug targeting BRAF, has been performed by (Sommariva et al, 2021b). The obtained results have been extensively compared with results previously published in literature.…”