Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ras-Raf-MEK-ERK signalling pathway is frequently dysregulated in human malignancies, as is angiogenesis and the vascular endothelial growth factor receptor (VEGF/VEGFR) pathway. These kinases are therefore important anticancer targets. The novel, oral treatment sorafenib (BAY 43-9006), has been shown to be an inhibitor of VEGFR, Raf and platelet-derived growth factor in clinical trials against a variety of cancers, with the greatest activity to date observed in metastatic renal cancer. Although side-effects with this targeted therapy are usually not dose-limiting, they frequently involve the skin, and consist of a maculopapular rash, palmar-plantar dysaesthesia, alopecia and xerosis. In this report, we present two patients in whom treatment with sorafenib resulted in inflammation of actinic keratosis, which in some cases progressed to invasive squamous cell carcinoma. This side-effect is of clinical importance, as early recognition is critical for early treatment and may represent a source of additional morbidity to these patients.
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PMID:Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. 1682 50

Paroxysmal drug-induced acne is a peculiar condition recognized for decades in dermatology. It can be induced by a variety of drugs. In recent years, the epidermal growth factor receptor inhibitors used in oncology have shown this type of adverse effects. The pathogenic mechanism is likely related to the EGF implication in the rupture of the microcomedo wall resulting in the perifollicular inflammatory reaction typical for acne. Other cutaneous adverse effects have been reported with anti-EGFR drugs including paronychia and xerosis. The dermatological treatments of these drug-induced disorders must be adequately targeted.
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PMID:[Paroxysmal iatrogenic acne and the epidermal growth factor receptor inhibitors (EGFR)]. 1734 23

This review summarizes the pathophysiology and clinical presentation of the cutaneous toxicities associated with EGFR inhibition. Such effects include papulopustular reactions, xerosis, pruritus, fissures, nail changes, hair changes, telangiectasias, hyperpigmentation, and mucositis. Most management strategies for these toxicities have been based on anecdotal experience; clinical trials are needed to provide uniform characterization to allow for evidence-based treatment strategies.
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PMID:Clinical presentation and pathophysiology of EGFRI dermatologic toxicities. 1815 12

Lung cancer is the leading cause of cancer-related death worldwide. Despite several chemotherapeutic agents, a survival plateau has been reached, so new treatment strategies are clearly needed. A strong interest is now focused on the use of targeted therapies for the management of non-small-cell lung cancer. Monoclonal antibodies against the epidermal growth factor receptor (EGFR; cetuximab) or vascular endothelial growth factor receptor (VEGFR; bevacizumab) and EGFR tyrosine kinase inhibitors (gefitinib, erlotinib) are generally well tolerated and do not have the severe systemic side effects usually seen with cytotoxic drugs. A considerable number of treated patients develop dermatologic side effects, such as acneiform eruption, xerosis, and eczema, and unfortunately, this is often one cause of negative impact on a patient's quality of life. No controlled clinical trials have been performed to manage rash, so it is necessary to provide suggestions for managing this frequent side effect. The main problems related to the class of angiogenesis inhibitors affecting VEGFRs are the exclusion of patients with brain metastases and/or squamous histology, and vascular adverse effects, such as hypertension, proteinuria, thrombosis, and hemorrhage. There are other new agents in clinical development, such as sorafenib, sunitinib, vorinostat, vandetanib, everolimus, panobinostat, and ASA404. They are all associated with a spectrum of toxicities, often reversible with interruption of dosing. Further research is required to clarify the role of targeted therapies and toxicities management.
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PMID:Toxicity of targeted therapy in non-small-cell lung cancer management. 1928 69

Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as the cause of the common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried by up to 10% of people, also represent a strong genetic predisposing factor for atopic eczema, asthma and allergies. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the approximately 400 kDa profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases to form monomeric filaggrin (37 kDa), which binds to and condenses the keratin cytoskeleton and thereby contributes to the cell compaction process that is required for squame biogenesis. Within the squames, filaggrin is citrullinated, which promotes its unfolding and further degradation into hygroscopic amino acids, which constitute one element of natural moisturising factor. Loss of profilaggrin or filaggrin leads to a poorly formed stratum corneum (ichthyosis), which is also prone to water loss (xerosis). Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens. Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.
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PMID:Filaggrin in the frontline: role in skin barrier function and disease. 1938 95

Epidermal growth factor receptor inhibitors (EGFRIs) are new anticancer agents that act by inhibiting EGFR signaling transduction pathways, thus decreasing tumor growth. In more than 30 countries, EGFRIs are currently used in the treatment of a number of solid tumors, and other indications are being sought. In the United States, select EGFRIs have been approved in certain patients with non-small cell lung cancer, metastatic colorectal carcinoma, and advanced squamous cell carcinoma of the head and neck. Various cutaneous side effects of EGFRIs have been reported, including acneiform eruptions, chronic paronychia, xerosis, a seborrheic dermatitis-like eruption, changes in hair texture, and nonscarring alopecia. We present a 60-year-old woman with non-small cell lung cancer who developed a persistent generalized itchy eruption and progressive nonscarring alopecia shortly after initiation of erlotinib (Tarceva). Scalp biopsy showed near-equal number of anagen and catagen/telogen hair follicles, and a superficial and deep perivascular lymphoplasmocytic infiltration. These changes are typical of the nonscarring alopecia induced by EGFRIs. Because it is likely that EGFRIs will be increasingly used, dermatopathologists are likely to see more reactions from these agents. Familiarity with their side effects is essential to accurate diagnosis and effective patient management.
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PMID:A case report of inflammatory nonscarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib. 1951 75

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late-stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS-RAF-MEK-ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management.
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PMID:Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. 2254 Jan 51

There is a variety of adverse effects and toxicities of newer and older chemotherapeutic agents which emerge in the skin, mucosa and adnexa. Common skin reactions while undergoing chemotherapy include alopecia, changes in skin pigmentation, palmoplantar erythrodysesthesia, nail dystrophies and stomatitis. Extravasation injuries or hypersensitivity reactions may be severe. New oncologic agents have led to the development of different, class-specific cutaneous side effects. Epidermal growth factor receptor (EGFR) inhibitors induce papulopustular rashes in a high percentage of patients as well as, to a smaller degree, xerosis cutis, hair and nail changes, hyper pigmentation and enhancement of radiation dermatitis. Multikinase inhibitors will often cause hand-foot syndrome, but may also induce facial erythema, subungual splinter hemorrhages and other less frequent skin changes. BRAF inhibitors can lead to rash and development of cutaneous keratinocytic neoplasias for which patients should be closely monitored. Finally, MEK/ERK inhibitors induce similar skin toxicities to EGFR inhibitors such as papulopustular rashes, xerosis cutis and paronychia. Our chapter will focus on the clinical picture, histopathology and treatment options of these new class-specific cutaneous side effects.
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PMID:Cutaneous drug eruptions associated with the use of new oncological drugs. 2261 63

The development of targeted therapies has ushered in a new era in the management of melanoma. Inhibitors of the RAS-RAF-MEK-ERK pathway have taken the center stage with development at a rapid pace. Vemurafenib was recently approved by regulatory agencies, and other agents (e.g. dabrafenib) are in various stages of clinical testing. These agents are producing remarkable results for patients, but are also presenting new challenges. Clinical toxicities and drug resistance are topmost issues. Some of the most common and vivid representations of adverse events to these agents are the dermatologic manifestations. Published trials and initial observations reflect a toxicity profile (e.g. squamous cell carcinomas/keratoacanthomas, maculopapular rashes, hyperkeratosis) that is distinct from cutaneous toxicities from EGFR and mTOR inhibitors (acneiform rash, paronychia, xerosis). Their management extends beyond conservative treatment and includes specific physical and surgical treatment modalities, skill sets unique to dermatologists. All these pose significant challenges to clinicians, and sound knowledge of such toxicities and their management will likely result in improved patient outcomes and quality of life. In this manuscript, we provide an overview of the emerging scientific literature on dermatological adverse events arising out of BRAF inhibition.
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PMID:Dermatological adverse events from BRAF inhibitors: a growing problem. 2346 15

Dermatologic adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as ErbB1) tyrosine kinase inhibitor therapy. The impact of these AEs goes beyond cosmesis to the discomfort from itching, pain and secondary infections, all of which may significantly impact on patient well-being, adherence and clinical outcomes. Afatinib is a potent, irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to EGFR inhibitors, dermatologic AEs have been frequently observed in patients treated with afatinib. Papulopustular (acneiform) rash, pruritus, xerosis, paronychia and alopecia will require patient education and proactive treatment interventions. This article summarizes current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program, and provides strategies for their effective management.
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PMID:Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. 2350 19


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