Dataset Information

Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor.

ABSTRACT: Epidermal growth factor receptor (EGFR) inhibitors are widely used in the treatment of cancer. EGFR-targeted treatment is known to be associated with a high incidence of dermatological adverse reactions, including papulopustular rash, which can be dose-limiting and may affect compliance to treatment. Currently, the pathways involved in EGFR inhibitor-induced rash are poorly understood and few treatment options for this adverse event are available. Here, we developed a model for induction of papulopustular rash in healthy human volunteers by subcutaneous injection of the anti-EGFR monoclonal antibody zalutumumab. The injection sites and surrounding skin were evaluated by a dermatologist for the presence or absence of papulopustular rash and skin biopsies were taken to confirm the macroscopical findings by immunohistochemistry. Locally injected zalutumumab induced a papulopustular rash, characterized by acute follicular neutrophil-rich hair follicle inflammation, and thus mimicked adverse events induced by systemic administration of EGFR inhibitors. In this model, we tested the hypothesis that neutrophils, attracted by IL-8, play a central role in the observed rash. Indeed, concomitant local repeat dose treatment with HuMab-10F8, a neutralizing human antibody against IL-8, reduced the rash. Inhibition of IL-8 can therefore ameliorate dermatological adverse events induced by treatment with EGFR inhibitors.

SUBMITTER: Bangsgaard N

PROVIDER: S-EPMC3382563 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor.

Bangsgaard Nannie N Houtkamp Mischa M Schuurhuis Danita H DH Parren Paul W H I PW Baadsgaard Ole O Niessen Hans W M HW Skov Lone L

PloS one 20120625 6

Epidermal growth factor receptor (EGFR) inhibitors are widely used in the treatment of cancer. EGFR-targeted treatment is known to be associated with a high incidence of dermatological adverse reactions, including papulopustular rash, which can be dose-limiting and may affect compliance to treatment. Currently, the pathways involved in EGFR inhibitor-induced rash are poorly understood and few treatment options for this adverse event are available. Here, we developed a model for induction of papu ...[more]

PMID: 22761877

Similar Datasets

Project description:Fibroblast growth factor receptor (FGFR) tyrosine kinases, which are expressed on the cell membrane, are involved in a wide range of biological functions such as cell proliferation, survival, migration, and differentiation. The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example, infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib. In addition to the typical adverse events associated with tyrosine kinases, the FGFR inhibitors appear to give rise to a number of adverse events affecting the skin. Here we describe these skin events, which include the more common nail adverse events (e.g., onycholysis), palmar-plantar erythrodysesthesia syndrome, and stomatitis, as well as less common reactions such as calciphylaxis. This review aims to provide oncologists with an understanding of these dermatologic events and proposes guidelines for the management of treatment-emergent dermatologic adverse events. Awareness of possible adverse events associated with specific drugs should allow physicians to educate patients as to what to expect and implement effective management plans at the earliest possible opportunity, thereby preventing premature discontinuation while maintaining patient quality of life. IMPLICATIONS FOR PRACTICE: Identification of fibroblast growth factor receptor (FGFR) aberrations in cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles. The most frequent adverse events (AEs) include those affecting skin, hair, and nails, a unique class effect of these agents. These are usually mild to moderate in severity. This work reviewed skin AEs reported with FGFR inhibitors and provides management guidelines for physicians, aiming to increase awareness of skin events and provide effective treatment strategies. Early intervention and effective management may improve treatment adherence, optimize outcomes, and improve quality of life.

Project description:Chronic kidney disease (CKD) increases the risk of cardiovascular disease, including vascular calcification, leading to higher mortality. The release of calcifying extracellular vesicles (EVs) by vascular smooth muscle cells (VSMCs) promotes ectopic mineralization of vessel walls. Caveolin-1 (CAV1), a structural protein in the plasma membrane, plays a major role in calcifying EV biogenesis in VSMCs. Epidermal growth factor receptor (EGFR) colocalizes with and influences the intracellular trafficking of CAV1. Using a diet-induced mouse model of CKD followed by a high-phosphate diet to promote vascular calcification, we assessed the potential of EGFR inhibition to prevent vascular calcification. Furthermore, we computationally analyzed 7,651 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham cohorts to assess potential correlations between coronary artery calcium and single-nucleotide polymorphisms (SNPs) associated with elevated serum levels of EGFR. Mice with CKD developed widespread vascular calcification, associated with increased serum levels of EGFR. In both the CKD mice and human VSMC culture, EGFR inhibition significantly reduced vascular calcification by mitigating the release of CAV1-positive calcifying EVs. EGFR inhibition also increased bone mineral density in CKD mice. Individuals in the MESA and Framingham cohorts with SNPs associated with increased serum EGFR exhibit elevated coronary artery calcium. Given that EGFR inhibitors exhibit clinical safety and efficacy in other pathologies, the current data suggest that EGFR may represent an ideal target to prevent pathological vascular calcification in CKD.NEW & NOTEWORTHY Here, we investigate the potential of epidermal growth factor receptor (EGFR) inhibition to prevent vascular calcification, a leading indicator of and contributor to cardiovascular morbidity and mortality. EGFR interacts and affects the trafficking of the plasma membrane scaffolding protein caveolin-1. Previous studies reported a key role for caveolin-1 in the development of specialized extracellular vesicles that mediate vascular calcification; however, no role of EGFR has been reported. We demonstrated that EGFR inhibition modulates caveolin-1 trafficking and hinders calcifying extracellular vesicle formation, which prevents vascular calcification. Given that EGFR inhibitors are clinically approved for other indications, this may represent a novel therapeutic strategy for vascular calcification.

Dataset Information

Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor.

Publications

Neutralization of IL-8 prevents the induction of dermatologic adverse events associated with the inhibition of epidermal growth factor receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets