Tumor Necrosis Factor-α and Interleukin-1 Antagonists Alleviate Inflammatory Skin Changes Associated with Epidermal Growth Factor Receptor Antibody Therapy in Mice

Abstract

Cancer patients receiving epidermal growth factor receptor (EGFR) antibody therapy often experience an acneiform rash of uncertain etiology in skin regions rich in pilosebaceous units. Currently, this condition is treated symptomatically with very limited, often anecdotal success. Here, we show that a monoclonal antibody targeting murine EGFR, ME1, caused a neutrophil-rich hair follicle inflammation in mice, similar to that reported in patients. This effect was preceded by the appearance of lipid-filled hair follicle distensions adjacent to enlarged sebaceous glands. The cytokine tumor necrosis factor-A (TNFA), localized immunohistochemically to this affected region of the pilosebaceous unit, was specifically upregulated by ME1 in skin but not in other tissues examined. Moreover, skin inflammation was reduced by cotreatment with the TNFA signaling inhibitor, etanercept, indicating the involvement of TNFA in this inflammatory process. Interleukin-1, a cytokine that frequently acts in concert with TNFA, is also involved in this process given the efficacy of the interleukin-1 antagonist Kineret. Our results provide a mechanistic framework to develop evidence-based trials for EGFR antibody-induced skin rash in patients with cancer.

Histopathologic and Immunohistochemical Characterization of Rash to Human Epidermal Growth Factor Receptor 1 (HER1) and HER1/2 Inhibitors in Cancer Patients

“…All of these findings have also been observed in our analyzed samples. These findings have also been shown in mice treated with an anti-EGFR monoclonal antibody, where follicular plugging with increased sebaceous gland size and a neutrophilic follicular infiltrate are observed (22). Enlargement of sebaceous units was not detected in our patients, which could potentially relate to timing of biopsies.…”

“…There is also some evidence that these agents may also alter the immune system (21). More recently, a preclinical model showed the role of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in the development of HER1i-associated skin rash and suggested a possible therapeutic role for anti-TNF agents (22). Several studies have aimed to identify histologic and immunohistochemical features of skin in patients undergoing therapy with HER1 inhibitors.…”

The Phosphatase Inhibitor Menadione (Vitamin K3) Protects Cells from EGFR Inhibition by Erlotinib and Cetuximab

“…The treatment of the skin toxicity secondary to EGFR inhibitors has until recently been mostly empirical, consisting of the use of topical skin moisturizers, topical sunscreens, and topical and systemic anti-inflammatory agents and antibiotics (32)(33)(34). The use of topical steroids and immunosuppressant agents has not been clearly shown to be of clinical value.…”

Increased Fanconi C expression contributes to the emergency granulopoiesis response

“…We tested IL-1R blockade as an approach to protecting Fancc -/-mice from bone marrow failure during repeated emergency granulopoiesis challenge. We used an IL-1R antagonist (anakinra) that is FDA approved for human subjects with autoimmune disorders and has been previously used in murine models (43,49). We found that treatment with anakinra blocked emergency granulopoiesis in WT mice and ameliorated bone Stable transfectants.…”