Lastly, skin toxicity remains a common side effect that frequently causes the discontinuation of the drug. Other common side effects to EGFR inhibitors also include perturbations to the colon and cornea. The G arrest appears to be due to the upregulation of pKIP activity. Pharmacological inhibition of EGFR is highly benecial to radiotherapy, as ionizing radiation can actually stimulate EGFR and activate its cryoprotective signaling cascades.For example, colorectal cancers often acquire resistance to cetuximab and panitumumab treatment. MEK is a convergence point of aberrant activation from potent upstream signaling proteins, and due to its narrow substrate specicity, makes it a favorable target for therapeutical intervention.Two direct inhibitors of MEK, trametinib and cobimetinib, have been approved by the FDA for melanoma treatment. The combinatorial treatment of MEK and EGFR inhibitors appears to overcome the acquired resistance to the EGFR inhibitors. No PIK or AKT inhibitors have reached the bedside so far, although three mTOR inhibitors have been approved by the FDA. However, inhibition of EGFR family members by PIK signaling does not rely on IRS.These mechanisms of RTK upregulation when challenged with PIK pathway inhibition maintains receptor activity, which produce more PIP to compensate for a loss of downstream signaling.In this section, we will examine the mechanisms by which the EGFR initiates cell cycle progression, including its upregulation of CYCLIN D, and downregulation of cyclindependent kinase inhibitor proteins. We will also examine the rationale for combining CDK and EGFR inhibitors, as this combination has been of recent interest. A pulse of EGF stimulation during early G and another at late G are sufcient to drive cells past the restriction point, the instant at which the cell commits to the completion of the cell cycle. In cancers, activating mutations to the EGFR are <a href="https://www.ncbi.nlm.nih.gov/pubmed/20266021">sell
Tannic acid</a> correlated with higher expression levels of CYCLIN D. These types of cancers also have lower patient prognostic values.Constitutively active oncogenic EGFR uses these pathways to continuously drive cells past the R point to promote hyperplasia.The ERK pathway induces CYCLIN D expression through its activation of the AP complex.AKT also upregulates CYCLIN D activity through the inactivation of GSK. GSK is normally active in quiescent cells, and downregulates CYCLIN D activity in two ways.First, active GSK causes CYCLIN D proteolysis by phosphorylating it at T, which mediates its nuclear export and degradation. In the same way, GSK can mediate the degradation of another cyclin, CYCLIN E, by phosphorylation at S. In response to EGF, GSK is phosphorylated by AKT at S and inactivated, allowing the transcription of CYCLIN D and the stabilization of both CYCLIN D and CYCLIN E. The activation of eIFE results from ERK phosphorylation of MNK at T and T, which then phosphorylates eIFE at S. Since CYCLIN D activates CDK to drive G progression, selective CDK inhibitors have been of intense recent research, driven by the availability of highly specic CDK inhibitors that also exhibit low patient toxicity and high tolerability. These include the oral drugs palbociclib, abemaciclib, and LEE, with both palbociclib and LEE having been recently approved for breast cancer in combination with letrozole, an aromatase inhibitor.