Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The success of the RAF protein kinase inhibitor vemurafenib for the treatment of BRAF mutant metastatic melanoma has produced another poster child for the promise of personalized medicine. However, the results of a recent study also reveal unexpected pitfalls in the application of signal transduction-targeted therapies.
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PMID:The RAF inhibitor paradox revisited. 2234 May 88

Vemurafenib, a selective BRAF kinase inhibitor, is a new anti-cancer drug recently proven to improve survival in patients with metastatic melanoma harboring the BRAF V600E mutation. BRAF is one of three RAF kinases (ARAF, BRAF, CRAF) involved in the MAP kinase pathway. Mutations in BRAF are reported to be present in 40 to 70 percent of melanomas and in lower frequencies in various other malignancies. The BRAF V600E mutation is a specific valine to glutamic acid single substitution that constitutes 80 to 90 percent of reported BRAF mutations. Successful treatment of metastatic melanoma with vemurafenib is not without significant adverse effects. The most common toxic effects of this drug include rash, arthralgia, and fatigue. Less commonly, cases of follicular cystic lesions, keratoacanthoma, and squamous cell carcinoma have also been described. We report a case of a patient with metastatic melanoma treated with vemurafenib, who developed diffuse follicular hyperkeratosis resembling keratosis pilaris. To our knowledge, this is the first reported case of a keratosis pilaris-like side effect of vemurafenib.
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PMID:A case of vemurafenib-induced keratosis pilaris-like eruption. 2255 22

Dermatologic toxicities associated with anticancer-targeted therapy include hand-foot skin reactions, vasculitis, cutaneous epithelial proliferations, such as keratosis, keratoacanthoma, and invasive squamous cell carcinoma. In this case report, we describe alterations of tumor morphology and patterns of cyclin-dependent kinase inhibitor (CDKI) expression in a patient who received GSK2118436, a second-generation RAF inhibitor, for stage IV (M1c) metastatic melanoma. To explore the effects of GSK2118436 on the expression patterns of CDKI (p16, p21, p27, p57), we immunohistochemically evaluated in vivo melanoma cells pre- and posttreated with GSK2118436. After GSK2118436 treatment, the melanoma cells decreased in size and demonstrated hyperchromatic nuclei and indistinct nucleoli. p16 was strongly expressed in the cytoplasm of pretreated melanoma cells and in the nucleus and cytoplasm in posttreated melanoma cells. Expression of both p27 (nucleus) and p57 (cytoplasm) was increased in posttreated melanoma cells and no significant difference in p21 expression was noted in either pre- or posttreated tumor cells. These findings may help explain the molecular mechanisms by which tumor cells retain the ability to proliferate. The persistent activation of pro-oncogenic activities of CDKI (eg, p27 and p57) and/or compartmentalization of p16 in cytoplasm or nucleus may allow tumor cells to bypass BRAF-induced senescence mechanisms. Furthermore, awareness of changes in tumor morphology after treatment with RAF inhibitors may be helpful in histologic evaluation of the spectrum of dermatologic toxicity, which may occur on targeted therapy.
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PMID:Changes in tumor morphology and cyclin-dependent kinase inhibitor expression in metastatic melanoma treated with selective second-generation BRAF inhibitor. 2287 67

BACKGROUND Therapy with vemurafenib, an inhibitor of mutated BRAF, yields a response rate of approximately 50% in patients with metastatic melanoma harboring a BRAF V600E mutation. As an adverse effect of vemurafenib, proliferative disorders of keratinocytes, including squamous cell carcinoma, have been described. Low concentration of vemurafenib as present in the epidermis were found to activate wild-type RAF, which, in combination with a preexisting RAS mutation, can promote keratinocyte proliferation. While activating BRAF mutations occur in approximately 50% of melanomas, they are even more frequently observed in melanocytic nevi. OBSERVATION We present the case of a patient with dynamic changes of melanocytic nevi well documented by sequential digital dermoscopy during vemurafenib therapy. A variety of dermoscopic changes were observed. First, nevi involuted, and all of these originally showed a centrally elevated papillomatous and predominant globular pattern. Second, preexisting nevi increased in size, and pigmentation that rendered them atypical. Such lesions were flat and showed a predominant reticular pattern at baseline. Third, multiple new nevi occurred. One example of each of the latter 2 categories was excised and showed wild-type BRAF. CONCLUSION Our findings of changing nevi in a patient treated with vemurafenib highlight the need for sequential skin examinations, including dermoscopy.
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PMID:Dynamic changes in nevi of a patient with melanoma treated with vemurafenib: importance of sequential dermoscopy. 2291 Oct 96

Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, functions as a positive regulator of melanoma progression and metastasis. In contrast, the Raf kinase inhibitor, RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic melanoma cells. In this study, we explored a hypothesized inverse relationship between MDA-9 and RKIP in melanoma. Tumor array and cell line analyses confirmed an inverse relationship between expression of MDA-9 and RKIP during melanoma progression. We found that MDA-9 transcriptionally downregulated RKIP in support of a suggested cross-talk between these two proteins. Furthermore, MDA-9 and RKIP physically interacted in a manner that correlated with a suppression of FAK and c-Src phosphorylation, crucial steps necessary for MDA-9 to promote FAK/c-Src complex formation and initiate signaling cascades that drive the MDA-9-mediated metastatic phenotype. Finally, ectopic RKIP expression in melanoma cells overrode MDA-9-mediated signaling, inhibiting cell invasion, anchorage-independent growth, and in vivo dissemination of tumor cells. Taken together, these findings establish RKIP as an inhibitor of MDA-9-dependent melanoma metastasis, with potential implications for targeting this process therapeutically.
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PMID:Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma. 2306 33

Metastatic melanoma (MM) is a deadly skin disease refractory to standard chemotherapy. Despite numerous clinical and pathological parameters derived to guide patient management, clinical outcomes in melanoma patients remain difficult to predict. There is a critical need to delineate the important biomarkers typical of this disease. These biomarkers will ideally illuminate those key biochemical pathways responsible for the aggressive behavior of melanoma and, in the process, unveil new opportunities for the design of rational therapeutic interventions in high-risk patients. The most common recurring mutation in cutaneous melanoma is the prooncogenic BRAF V600E mutation that drives melanoma cell proliferation. The development of RAF inhibitors targeted against BRAF V600E mutant melanoma cells has revolutionized the treatment of MM. Clinical trials with BRAF inhibitor vemurafenib have shown objective clinical response and improved survival in patients with MM; therefore, knowledge of the molecular signature of melanoma in patients will be important in directing management decisions. Several molecular platforms exist to analyze the mutation status of melanoma. These include Sanger sequencing, pyrosequencing, allele-specific reverse transcriptase polymerase chain reaction, mass spectrometry base sequencing (Sequenom), high-resolution melting curve analysis, and next-generation sequencing methods using microfluidics technology. The Food and Drug Administration has approved the cobas BRAF V600 Mutation Test developed by Roche to analyze BRAF mutation status in formalin-fixed paraffin-embedded tumor samples. The cobas Mutation Test has been designed specifically to detect BRAF V600E mutations, and the analytic performance of this assay has demonstrated >99% sensitivity in the detection of BRAF V600E mutation when compared with the Sanger sequencing method and confirmed with the next-generation sequencing 454-pyrosequencing technology. The lower limit of detection of the percentage of mutant alleles in a tissue sample for the cobas test is less than 4%-5%. Some cross-reactivity with other variants of mutant BRAF was seen with the cobas V600 platform; however, this clinical test offers highly sensitive reproducible BRAF V600E mutation analysis in formalin-fixed paraffin-embedded tumor samples.
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PMID:Molecular platforms utilized to detect BRAF V600E mutation in melanoma. 2317 97

FDA approval of new therapies in 2011 has greatly expanded the treatment options for metastatic melanoma. Patients with V600 mutant v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) positive metastatic melanoma are now treated with the RAF inhibitor, vemurafenib (Zelboraf) as a first line therapy. Vemurafenib decreases tumor size by at least 30% in approximately 50% of patients and increases progression-free survival and overall patient survival compared to the previous standard-of-care, dacarbazine. However, some patients treated with vemurafenib fail to show significant tumor shrinkage, and most patients who initially respond to the drug eventually show disease progression. Therefore, there is a clinical need to improve efficacy and prevent resistance to vemurafenib. It has been previously shown that cell death resulting from RAF/mitogen-activated protein kinase kinase (MEK) inhibition is largely dependent on increased expression of pro-apoptotic, Bcl-2 homology domain (BH3)-only proteins, such as Bcl-2-like 11 (Bim-EL) and Bcl-2 modifying factor (Bmf). Here, we show that contrary to expression of Bim-EL and Bmf, the pro-apoptotic, BH3-only protein, phorbol-12-myristate-13-acetate-induced protein 1 (Noxa), is strongly downregulated after RAF/MEK inhibition. This downregulation occurs at both the protein and mRNA level of expression and is associated with the inhibition of cell cycle progression. Restoring expression of Noxa in combination with RAF/MEK inhibition enhances cell death. Co-expression of the pro-survival, B-cell CLL/lymphoma 2 (Bcl-2) family member, myeloid cell leukemia sequence 1 (Mcl-1), with Noxa fully mitigates the enhanced cell death associated with increased Noxa expression. These data indicate that manipulating the Noxa/Mcl-1 axis may enhance the efficacy of RAF/MEK inhibitors.
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PMID:Downregulation of Noxa by RAF/MEK inhibition counteracts cell death response in mutant B-RAF melanoma cells. 2322 18

The RAF inhibitors vemurafenib and dabrafenib are emerging as the standard of care for Val600 BRAF-mutant metastatic melanoma. These drugs have shown clinical benefit over the standard care (dacarbazine); however, they are associated with frequent cutaneous adverse events, which can be concerning to the patient and their physician. Herein, we review the range of cutaneous disorders that seem to be induced by RAF inhibitors, including cutaneous squamous-cell carcinoma, hyperkeratotic lesions, Grover's disease, keratosis pilaris-like reactions, and photosensitivity. These disorders often affect patients' quality of life; therefore, dermatological assessment and timely management is essential to ensure that patients continue to use RAF inhibitors.
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PMID:Cutaneous toxicities of RAF inhibitors. 2327 66

The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increased HER3 signaling caused by induction of ERBB3 (HER3) transcription through decreased promoter occupancy by the transcriptional repressors C-terminal binding protein 1 and 2 and by autocrine secretion of neuregulin-1 (NRG1). The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands.
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PMID:Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. 2365 95

The RAS-RAF-MEK-ERK pathway is considered to be the most important signal transduction pathway in melanoma, and alterations in this pathway via various genetic mutations, such as BRAF and NRAS mutations, are known to be important drivers of melanomagenesis. As MEK is an essential intermediary kinase protein within this pathway, inhibition of MEK has been of a great interest as a molecular target therapy in melanoma. In fact, trametinib, a selective MEK inhibitor, has been shown to have a survival benefit over cytotoxic chemotherapy in patients with V600 BRAF-mutant metastatic melanoma, leading to the FDA approval for this patient population. MEK inhibitors may also be useful in treatment of advanced melanoma harboring other genetic mutations, such as NRAS and GNAQ/GNA11 mutations. Here, we review and discuss the preclinical and clinical data regarding MEK inhibitors and their role in the treatment of advanced melanoma.
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PMID:MEK inhibition in the treatment of advanced melanoma. 2397 10


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