ANTI-EGFR, what is the inside story (full story)

Could anti-EGFR effect be simply an intra-tumoral Vasculitis blocking vascular Oxygenation?  Can ANCA be a significant Biomarker particularly in those with Dermatitis? Is FAK and Metalloproteases be better biomarkers
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"The fact is that anti-EGFR activity is associated with a significant dermatitis.  And the dermatitis is associated or has been linked to drug activity.  Indeed the more severe the rash, the more the activity of the drug.  At skin level, we know as a result of the drug, toxic chemical are liberated to induce the reaction. 
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene.^[2] Myeloperoxidase is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells).^[3] It is a lysosomal protein stored in azurophilic granules of the neutrophil. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.

 As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H₂O₂) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation" wikipedia

Antibody " against MPO have been implicated in various types of vasculitis, most prominently crescentic glomerulonephritis and Churg-Strauss syndrome. They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are strongly associated with Wegener's granulomatosis. Recent studies have reported an association between myeloperoxidase levels and the severity of coronary artery disease.^[8] It has been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable."wikipedia

The above discussion bring to mind that dermatitis seen with use of Drugs aiming at epithelial covering  of blood vessel could indeed lead to secretion of molecules such as Cyclo-oxygenease (target of NSAID), MPO such as in this case Dapsone but Anti EGFR dose liberate from other affected cells cytokines of similar products that induced rash as a secondary effect.  Should study confirms that MPO is our guy, then ANCA would be a legitimate candidate Bio-Marker.
Certainly during the activity of anti-EGFR, there is significant mambranes activity in terms of shedding proteins/Cytokines, FAK will be over express as a function of this activity and high FAK will be expected, liberations of Metalloproteases and the ADAMS such as 12 will follow the same logic and could join biomarkers of EGFR activity.  Elevated stress at the membrane could be associated with HSP 90 amplification...let's go get them in a trial!

SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration.

Long W, Yi P, Amazit L, LaMarca HL, Ashcroft F, Kumar R, Mancini MA, Tsai SY, Tsai MJ, O'Malley BW.

Source

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA.

Abstract

EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src.