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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Patients treated with systemic anticancer drugs often show changes to their nails, which are usually well tolerated and disappear on cessation of treatment. However, some nail toxicities can cause pain and functional impairment and thus substantially affect a patient's quality of life, especially if they are given taxanes or EGFR inhibitors. These nail toxicities can affect both the nail plate and bed, and might present as melanonychia, leukonychia, onycholysis, onychomadesis, Beau's lines, or onychorrhexis, as frequently noted with conventional chemotherapies. Additionally, the periungual area (perionychium) of the nail might be affected by paronychia or pyogenic granuloma, especially in patients treated with drugs targeting EGFR or MEK. We review the nail changes induced by conventional chemotherapies and those associated with the use of targeted anticancer drugs and discuss preventive or curative options.
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PMID:Nail toxicities induced by systemic anticancer treatments. 2614 77

Targeted therapies for melanoma have shown clinical benefit in increasing the survival of metastatic patients. Cutaneous adverse events have been reported, but hair and nail data have been rarely detailed. Patients treated with BRAF and MEK inhibitors for metastatic melanoma underwent dermatological evaluation before the start of each treatment and after every four weeks. Pull test, global photography, dermoscopy/trichoscopy and scalp biopsy were performed. Appendages adverse events were graded using the National Cancer Institute's Common Terminology Criteria. Of the 24 patients included, 14 underwent treatment with a selective BRAF inhibitor; 10 received a combined treatment (dabrafenib/trametinib). Adnexal adverse events were common in the group of patients receiving vemurafenib, and included hair kinking, acute hair loss, and hair colour changes, often present in association, classified as G2 in three patients and G1 in eight. Dabrafenib alone induced hair kinking and colour changes in 60% of the patients. Combined treatment with dabrafenib/trametinib did not induce hair changes. Onycholysis was the most common nail side effect, and the unique side effect of dabrafenib (alone or in combination). Vemurafenib also induced acute paronychia and brittle nails. All nail side effects were graded as G1. Hair and nail side effects during targeted therapy for melanoma are not rare. The early recognition and cure of such side effects by dermatologists is of benefit to ensure the need for dose reduction or drug discontinuation.
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PMID:Hair and nail adverse events during treatment with targeted therapies for metastatic melanoma. 2701 11

Overexpression of the epidermal growth factor receptor (EGFR) is found in many cancers, including those of the head and neck area, non-small-cell lung cancer, and colorectal, cervical, prostate, breast, ovary, stomach, and pancreatic cancer. The EGFR inhibitors are used at present in the treatment of such cancers. Skin lesions that develop during and after cancer treatment may be due to specific cytostatics, molecular-targeted drugs, radiation therapy, complementary therapy, or the cancer itself, and hence knowledge is essential to distinguish between them. The mechanism through which skin toxicity arises during treatment with EGFR inhibitors is not well known, but seems to be due to the modification of the RAS/RAF/MEK/ERK signal path associated with its activation, which results in the similarity between the adverse effects of EGFR inhibitors and the treatment of melanoma with BRAF and MEK inhibitors. The most common side effects are pruritus, xerosis, papulopustular rash, hand-foot skin reaction, alopecia and dystrophy of the hair, and paronychia. This work presents options for prevention and suggestions for managing these adverse events, which are of importance in the care of patients undergoing oncological treatment.
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PMID:The incidence and management of cutaneous adverse events of the epidermal growth factor receptor inhibitors. 2950 55

Paronychia is a painful inflammatory disorder of the nail fold. Periungual pyogenic granuloma - a benign vascular tumor of the capillaries - can develop as a complication of paronychia. We report both, paronychia and periungual pyogenic granuloma, as possible adverse events during systemic drug-therapy. The following groups of systemic drugs have been considered: taxanes, epidermal growth factor-receptor (EGFR) inhibitors, EGFR tyrosine kinase inhibitors, tyrosine kinase inhibitors, inhibitors of MEK/ERK, BRAF inhibitors, CD20 antagonists, vascular endothelial growth factor inhibitors, and retinoids. Recommendations for prevention and treatment are given. Since paronychia is a painful inflammatory disorder that has a negative impact on daily activities, early recognition and adequate treatment improve adhesion to treatment and quality of life.
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PMID:Systemic Drug-induced Chronic Paronychia and Periungual Pyogenic Granuloma. 3025 94

Targeted therapies and immunotherapies are associated with a wide range of dermatologic adverse events (dAEs) resulting from common signaling pathways involved in malignant behavior and normal homeostatic functions of the epidermis and dermis. Dermatologic toxicities include damage to the skin, oral mucosa, hair, and nails. Acneiform rash is the most common dAE, observed in 25-85% of patients treated by epidermal growth factor receptor and mitogen-activated protein kinase kinase inhibitors. BRAF inhibitors mostly induce secondary skin tumors, squamous cell carcinoma and keratoacanthomas, changes in pre-existing pigmented lesions, as well as hand-foot skin reactions and maculopapular hypersensitivity-like rash. Immune checkpoint inhibitors (ICIs) most frequently induce nonspecific maculopapular rash, but also eczema-like or psoriatic lesions, lichenoid dermatitis, xerosis, and pruritus. Of the oral mucosal toxicities observed with targeted therapies, oral mucositis is the most frequent with mammalian target of rapamycin (mTOR) inhibitors, followed by stomatitis associated to multikinase angiogenesis and HER inhibitors, geographic tongue, oral hyperkeratotic lesions, lichenoid reactions, and hyperpigmentation. ICIs typically induce oral lichenoid reactions and xerostomia. Targeted therapies and endocrine therapy also commonly induce alopecia, although this is still underreported with the latter. Finally, targeted therapies may damage nail folds, with paronychia and periungual pyogenic granuloma distinct from chemotherapy-induced lesions. Mild onycholysis, brittle nails, and a slower nail growth rate may also be observed. Targeted therapies and immunotherapies often profoundly diminish patients' quality of life, which impacts treatment outcomes. Close collaboration between dermatologists and oncologists is therefore essential.
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PMID:Toxic Side Effects of Targeted Therapies and Immunotherapies Affecting the Skin, Oral Mucosa, Hair, and Nails. 3037 1

Paronychia has been described as a side effect in patients undergoing treatment with MEK (mitogen activated protein kinase enzyme) inhibitors. It is usually a recurrent condition that can have a significant impact in the quality of life. Topical beta blocker treatment has been described as an effective therapy in antineoplastic-induced pyogenic granulomas and in antineoplastic-induced paronychia. We describe the first case treated with topical timolol for a trametinib-induced paronychia in a pediatric patient that allowed to continue the third line antineoplastic therapy for his glioma.
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PMID:Recalcitrant trametinib-induced paronychia treated successfully with topical timolol in a pediatric patient. 3170 90

Patients with neurofibromatosis type 1 (NF1) have an increased lifetime risk for the development of nervous system tumors, including high-grade gliomas (glioblastoma). NF1 is associated with the loss of expression of neurofibromin 1 (NF1 gene product). This hyperactivates the mitogen-activated protein kinase pathway, leading to cellular proliferation and survival. MEK-inhibitor monotherapy is a promising treatment strategy in this setting, but is associated with distinct adverse events, most prominently cutaneous toxicity. We report the case of a young NF1 patient with a recurrent, heavily pretreated mesencephalic glioblastoma who was treated with the MEK-inhibitor trametinib (2 mg once daily). A partial response was documented, but unfortunately, he developed dose-limiting cutaneous toxicity (rash, paronychia). Based on interim results of a phase 2 trial in advanced BRAF ^V600 wild-type melanoma indicating that a low dose of the BRAF-inhibitor dabrafenib is able to counter trametinib-related cutaneous toxicity, dabrafenib 50 mg twice daily was added. The cutaneous adverse events gradually recovered after addition of dabrafenib to trametinib. The patient eventually achieved a durable complete response, has excellent tolerance of his treatment and remains fully active.
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PMID:Durable Complete Response of a Recurrent Mesencephalic Glioblastoma Treated with Trametinib and Low-Dose Dabrafenib in a Patient with Neurofibromatosis Type 1. 3308 44


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