The capability of cancer cells to resist the growth inhibitory and cytotoxic actions of chemotherapeutic agents reflects their capability to undergo the equivalent of molecular evolution and create survival tactics. Several mechanism s are identified as currently being accountable for cancer cell chemo resistance drug Proteasome Proteases Gamma-secretase tolerance, these selection from acquisition of survival enhancing mutations in vital signaling molecules to ??switching?? in between different receptor driven signaling pathways, towards the induction of transporter protein expression enabling efflux of drug. As we probe deeper into the processes involved in drug resistance, it really is getting clear that extra mechanisms are at function. Within this evaluate, the basis for resistance to tyrosine kinase inhibitors TKIs might be talked about. These mechanisms will likely be compared and contrasted to resistance to receptor TKIs RTKIs and how these vary from what has become observed for monoclonal antibodies mAbs that target RTKs. Inside the latter case, we are going to consider the purpose of the IGF R being a dependence receptor and just how this may influence the response to TKIs vs. mAbs to yield resistance or therapeutic efficacy.
It is crucial to bear in mind the cells populating any given tumor are heterogeneous gsk3 wnt and that normal selection by drug dosing is often a crucial mechanism on this approach Cellular signaling pathways regulated by receptor and non receptor tyrosine kinases Receptor and non receptor tyrosine kinases use a number of popular effector proteins to mediate their downstream effects in normal and cancer cells.
As proven in Fig activation from the EGFR tyrosine kinase leads to stimulation of multiple downstream signaling pathways including Ras MAPK Erk , PIK Akt and Stat activation downstream with the Jak non receptor tyrosine kinase. Also, activation in the IGF R can lead to ??receptor cross speak?? consequently to protease activation and shedding of EGFR ligands or activation on the HIF transcription element resulting VEGF expression, consequently activating the EGFR and VEGFR, respectively Fig . Fig. illustrates signaling pathways regulated by Bcr Abl underscoring that common pathways to these regulated by RTKs are activated by this non receptor tyrosine kinase leading to enhanced cell proliferation, tumorigenesis, invasion and metastasis . The existence of overlapping or ??redundant?? pathways across receptor and non receptor kinases presents insight as to how compensatory signaling pathways take the place of individuals RTK pathways inhibited by a given molecularly targeted RTKI. These mechanisms, as well as kinase mutations, represent critical approaches through which cancer cells become resistant to targeted therapeutics and will be reviewed beneath commencing with Bcr Abl, TKIs and extending to a discussion of EGF and IGF receptors.