Results: 4

Figure 2

Figure 2. Resistance mechanisms originating from EGFR downstream effectors. From: Targeting EGFR resistance networks in Head and Neck Cancer.

Cell signaling effectors downstream of EGFR may mitigate the efficacy of EGFR inhibitors by maintaining signaling activity to drive cell cycle progression and inhibit apoptosis. Increased signaling of the PI3K-Akt pathway, STAT proteins and cell cycle progression mediators such as Cyclin D1 have been association with resistance to EGFR inhibitors in SCCHN. See text for details.

Vladimir Ratushny, et al. Cell Signal. ;21(8):1255-1268.
Figure 4

Figure 4. From: Targeting EGFR resistance networks in Head and Neck Cancer.

a. EGFR signaling drives cell survival and proliferation signals. EGFR transmits cell survival and proliferation signals through multiple downstream signaling pathways. Signals from EGFR are amplified due to both the density of interconnections in downstream signaling pathways and the parallel input provided from other membrane-bound growth factor receptor tyrosine kinases (RTKs).
b. Signaling mediators parallel or downstream to EGFR compensate for EGFR inhibition and limit the clinical efficacy of EGFR inhibitors. Inhibition of EGFR with targeted therapeutic antibodies or small molecule inhibitors has only limited clinical success. Resistance to EGFR inhibition develops due to the maintenance of cell survival and proliferation signals by activation of signaling effectors such as insulin-like growth factor I receptor (IGF-IR) which are parallel to EGFR or signaling effectors such as phosphoinositol-3-kinase (PI3K) which are downstream of EGFR.
c. Rational drug combination strategies are required to overcome EGFR resistance. Resistance to EGFR inhibitors in head and neck cancer may be overcome by treating patients with a combination of EGFR inhibitors and inhibitors of biological targets such as RTKs parallel to EGFR or protein kinases downstream of EGFR. Combined inhibition of EGFR and an EGFR-resistance mediator such as IGF-IR or PI3K will synergistically decrease cell survival and proliferation signals. In cancer cellswhich are dependent on EGFR signaling, such a combination drug treatment can cause cell cycle blockade and initiate apoptosis by increasing pro-apoptotic signals and decreasing anti-apoptotic signals. Thorough understanding of molecular mechanisms of EGFR resistance in an individual tumor is required to choose the correct combinational target and optimize the clinical efficacy of EGFR inhibitors.

Vladimir Ratushny, et al. Cell Signal. ;21(8):1255-1268.
Figure 3

Figure 3. Regulatory mechanisms operating at the level of the EGFR receptor and its ligands. From: Targeting EGFR resistance networks in Head and Neck Cancer.

I. Overexpression. Overexpression of EGFR in HNSCC has been linked to resistance to EGFR inhibitors. Mechanisms resulting in overexpression include increased EGFR copy number and mutations at the level of EGFR gene or promoter. II. Kinase domain mutations. Kinase domain mutations include in-frame deletions and amino acid substitutions centering around the ATP binding cleft of EGFR. These mutations lead to increased ligand-dependent activation of EGFR and increased sensitivity to EGFR inhibition by allowing easier access for both ATP substrate and competitive inhibitor. The prevalence of kinase domain mutations in head and neck cancer is low. III. EGFR vIII. EGFRvIII is a constitutively active form of the receptor, and has been associated with resistance to EGFR inhibitors in many SCCHNs. IV. Glycosylation. Glycosylation of EGFR contributes to ligand-induced receptor activation. In certain contexts, glycosylation status of EGFR may modify response to EGFR-targeted antibody and small molecule inhibitors. V. Ligand availability. The ADAM family of sheddases catalyzes the proteolytic reaction required for the releases the transmembrane precursors of EGFR ligands. Activation of ADAM-17 results in release of amphiregulin and is associated with activation of EGFR in HNSCC. In addition, amphiregulin expression predicts the sensitivity of SCCHN to inhibition by gefitinib and cetuximab. VI. Nuclear EGFR. Nuclear EGFR was shown to activate the transcription of the cell cycle progression mediator, cyclin D1. The mechanism of nuclear translocation and its importance as a sensitivity mediator to clinical EGFR inhibitors remains an area of active investigation.

Vladimir Ratushny, et al. Cell Signal. ;21(8):1255-1268.
Figure 1

Figure 1. Resistance mechanisms originating from parallel growth factor receptors. From: Targeting EGFR resistance networks in Head and Neck Cancer.

Growth factor receptors such as vascular endothelial growth factor receptor (VEGFR), insulin-like growth factor I receptor (IGF-IR), mesenchymal-epithelial transition factor (c-MET) provide compensatory activation of cell survival and proliferation pathways when EGFR is inhibited. Acting through a common adaptor molecule, Grb2, IGFR, c-MET and EGFR drive proliferation and cellular survival signals by activating the Ras>Raf>MEK>Erk axis. VEGFR also activates this signaling cascade via the phospholipase C-γ (PLC- γ) mediated activation of protein kinase C (PKC) which in turn activates Raf. The phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling axis is activated by either direct association of PI3K to the cytoplasmic domain of tyrosine kinase receptors or via adaptor molecules such as insulin receptor substrate 1 (IRS1) or Grb2-associated binding protein 1 (Gab1). Signal Transducers and Activator of Transcription (STAT) are phosphorylated by EGFR, EGFR-interactor Src, and adjacent growth factor receptors (c-MET). The phosphorylated forms of STAT translocate to the nucleus and activate the transcription of genes involved in cell cycle progression, angiogenesis and apoptotic resistance. Other members of the ErbB family can compensate for inhibition of EGFR signaling by dimerizing amongst themselves to activate an overlapping set of downstream effectors. mTor denotes mammalian target of rapamycin; Sos, son of sevenless; Grb2, growth factor receptor-bound protein 2; MEK, MAPK kinase; Erk, extracellular signal-regulated kinase.

Vladimir Ratushny, et al. Cell Signal. ;21(8):1255-1268.

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