The pAKT dose response to HRG, pAKT , showed a switch like behaviour much like pHER . Maximal activation of AKT signal occurswithin a narrowrange of HRG concentration and its saturation is attained in the concentration of HRG equal to . nM . Consequently the two RSS and SN deliver the results in saturation mode at HRG concentration higher than nM. The dose dependences of the output signal of RSS, pHER , as well as the output signal of SN, pAKT , on pertuzumab concentration are proven in Fig. B . The main difference between these output signals is determined by the inherent dose response traits within the STS . The inhibition of HER receptor by nM pertuzumab leads to inhibition of RTK, pHER and inhibition of pAKT . To model HER overexpression we enhanced fold the concentration of HER receptor. Note that the original HER HER ratio from the model equals that is near to a current experimental measure to the PE cell line . HER overexpression triggers a shift inside the pHER and pAKT dose dependences for pertuzumab to higher concentrations . This impact prospects to an increase of approximately occasions for pHER EC and pAKT IC, and this inhibition of pHER triggers inhibition of pAKT .
These benefits display that overexpression of HER brings about insensitivity from the RSS and the total SN to pertuzumab inside the physiological array of pertuzumab concentrations . To review pHER and pAKT responses to pertuzumab inside a wide variety of chemical library HER expression amounts, we calculated pHER and pAKT dose dependences on HER concentration inside the presence and absence of nM pertuzumab . At HER nM the RSS and SN get the job done in saturation mode inside the absence of pertuzumab and non saturation mode in the presence of pertuzumab . With a rise in overexpression of HER by two orders ofmagnitude, RSS and SN return to function close to saturation mode while in the presence of nM of pertuzumab . Note that in our model we don’t look at the ligand independent activation of HER as a result of HER homodimerization at HER overexpression , and concentrate for the HER HER activation in the PIK PTEN AKT pathway. Because of this, we propose that a fold HER enhance won’t adjust the kinetics of receptor HER HER heterodimerization and also the position of HER homodimerization in AKT activation is insignificant.
Our calculation relates to the situation of the lesser level of HER overexpression happening by transcriptional translational mechanisms without gene amplification . An extension to our model is required to describe and explain the results of ligand independent activation of HER on trastuzumab and pertuzumab resistance and anomalous phosphorylation Imiquimod of HER in the action of trastuzumab and pertuzumab at HER amplification. To analyse the sensitivity of RSS to pertuzumab, we in contrast RSS sensitivities to the first concentrations of receptors and their kinetic parameters, SRSS,i, in the absence and presence of nM pertuzumab.