The strange connection between epidermal growth factor receptor tyrosine kinase inhibitors and dapsone: from rash mitigation to the increase in anti-tumor activity

Abstract

The presence of an aberrantly activated epidermal growth factor receptor (EGFR) in many epithelial tumors, due to its overexpression, activating mutations, gene amplification and/or overexpression of receptor ligands, represent the fundamental basis underlying the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Drugs inhibiting the EGFR have different mechanisms of action; while erlotinib and gefitinib inhibit the intracellular tyrosine kinase, monoclonal antibodies like cetuximab and panitumumab bind the extracellular domain of the EGFR both activating immunomediated anti-cancer effect and inhibiting receptor function. On the other hand, interleukin-8 has tumor promoting as well as neo-angiogenesis enhancing effects and several attempts have been made to inhibit its activity. One of these is based on the use of the old sulfone antibiotic dapsone that has demonstrated several interleukin-8 system inhibiting actions. Erlotinib typically gives a rash that has recently been proven to come out via up-regulated keratinocyte interleukin-8 synthesis with histological features reminiscent of typical neutrophilic dermatoses. In this review, we report experimental evidence that shows the use of dapsone to improve quality of life in erlotinib-treated patients by ameliorating rash as well as short-circuiting a growth-enhancing aspect of erlotinib based on increased interleukin-8 secretion.

A prospective, randomized, double-blinded, split-face/chest study of prophylactic topical dapsone 5% gel versus moisturizer for the prevention of cetuximab-induced acneiform rash

“…Dapsone exerts its anti-inflammatory effects via suppression of neutrophil recruitment, inhibition of the release of prostaglandins and leukotrienes and lipopolysaccharide stimulated IL-8 production in human keratinocytes, 2,3 and a decrease of mononuclear cell TNF-α production. 4,5 It also blocks the generation of toxic, oxygen-derived radicals, thereby protecting against neutrophil- and eosinophil-mediated injury.…”

Paths for Improving Bevacizumab Available in 2018: The ADZT Regimen for Better Glioblastoma Treatment

“…In addition to antibacterial activity in treating Hansen's disease and pulmonary tuberculosis, dapsone has anti-protozoal effects and is used currently in treating Plasmodia infections. Unrelated to antibiotic activity, dapsone has found some utility in treating neutrophilic dermatoses like bullous pemphigoid, dermatitis herpetiformis, and others [33] including the neutrophilic rash caused by epidermal growth factor receptor inhibiting drugs [34,35]. In a series of six papers my colleagues and I have amply documented the rationale for using dapsone to deprive the tumors of neutrophil-delivered VEGF during the treatment of glioblastoma [36][37][38].…”

Dapsone as treatment adjunct in ARDS

“…25,26 This use led to the discovery that dapsone ameliorates these dermatoses primarily by inhibiting neutrophil migration along an IL-8 gradient. [27][28][29][30][31][32][33][34][35][36][37] Proof that the characteristic rash caused by erlotinib was mediated by IL-8 in turn led to dapsone use in treating that neutrophilic rash. 29,31,38 In vitro study showed dapsone inhibited neutrophil chemotaxis to both N-formylmethionyl-leucylphenylalanine and to IL-8 via interference with neutrophils' adherence functions.…”