Apr 10, 2012

PI3K/PTEN/AKT signalling network

Techniques biology approaches which bundle experimental information and also theoretical modeling to understand mobile signalling network dynamics provide valuable platform to investigate the mechanisms of resistance to drug treatments and additionally to identify combo drug treatments. Extending the work at modeling the PI3K/PTEN/AKT signalling network (SN), we analyze the sensitiveness of the SN result signal, phospho-AKT, to inhibition of HER2 receptor. We model typical aberrations in this SN identified in cancer development and additionally drug resistance: reduced PTEN activity, PI3K and also AKT mutations, HER2 complete expression, and complete creation of GSK3 and CK2 kinases controlling PTEN phosphorylation. We program that HER2inhibition by the monoclonal antibody pertuzumab increases SN sensitiveness, simultaneously to outside tells and also to changes in kinetic parameters of the proteins and their appearance levels induced with mutations in the SN. This increase in sensitiveness comes from the transition of SN operating from saturation to non-saturation mode in reaction to HER2 inhibition. PTEN reduction or alternatively PI3CA change causes resistance to anti-HER2 inhibitor and additionally guides to the restoration of saturation mode in SN working having a consequent reduce in SN susceptibility. We advise the fact that a drug-induced rise in SN sensitiveness to internally perturbations, and additionally specifically mutations, causes SN delicacy. In specific, the SN is open to mutations which make up for drug action as well as this might cause a sensitivity-to-resistance transition. The blend of HER2 and also PI3K inhibition does not sensitize the SN to internally perturbations (mutations) in the PI3K/PTEN/AKT pathway: this combination treatment offers simultaneously synergetic inhibition and could very well avoid the SN from using acquired mutations causing drug resistance. Through combination inhibition treatments, you researched the impact of upstream and additionally downriver interventions to suppress resistance to the HER2 chemical in the SN alongside PTEN loss. Assessment of experimental outcomes of PI3K inhibition in the PTEN upstream pathway alongside PDK1 inhibition within the PTEN downstream pathway tv series the fact that upstream inhibition abrogates resistance to pertuzumab a lot more effectively as compared to downriver inhibition. This difference in inhibition effect comes from the compensatory mechanism of an activation loop induced in the downstream pathway by PTEN loss. We highlight which drug target identification for combination anti-cancer treatment must account for the mutation effects found on the upstream and additionally downstream paths.

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