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

The RAS-RAF-MEK-ERK signalling pathway is hyperactivated in a high percentage of tumours, most frequently owing to activating mutations of the KRAS, NRAS and BRAF genes. Recently, the use of compounds targeting components of ERK signalling, such as RAF or MEK inhibitors, has led to substantial improvement in clinical outcome in metastatic melanoma and has shown promising clinical activity in additional tumour types. However, response rates are highly variable and the efficacy of these drugs is primarily limited by the development of resistance. Both intrinsic and acquired resistance to RAF and MEK inhibitors are frequently associated with the persistence of ERK signalling in the presence of the drug, implying the need for more innovative approaches to target the pathway.
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PMID:Targeting RAS-ERK signalling in cancer: promises and challenges. 2543 14

One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.
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PMID:Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. 2545 14

Oncogenic BRAF mutations are present in approximately 40-50% of patients with metastatic melanoma. Targeting BRAF mutations with either small molecule inhibitors of BRAF or one of the downstream mediators of oncogenic BRAF - MEK - is associated with improved outcomes compared with chemotherapy and has led to the US FDA approval of two BRAF inhibitors - vemurafenib and dabrafenib - and the MEK inhibitor trametinib. Further, the combination of dabrafenib and trametinib is well tolerated and associated with higher responses and improved survival compared with single-agent BRAF inhibitors.
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PMID:Dabrafenib in combination with trametinib for the treatment of metastatic melanoma. 2547 43

Studies presented or published during the European Society for Medical Oncology conference demonstrate that combining BRAF and MEK inhibitors improves progression-free and overall survival--and lowers the risk of resistance and toxicities--in patients with metastatic melanoma with BRAF V600E or V600K mutations.
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PMID:Drug combos validated in BRAF-mutant melanoma. 2547 91

Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger-signalling resulting in surface mobilization of crucial damage-associated-molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger-signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger-signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re-establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib-resistant metastatic melanoma.
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PMID:Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells. 3208 47

The present "what's new in oncology in 2014?" is in keeping with data reported in the past years. Indeed, metastatic melanoma still keeps the lion's share. The results of the combinations schedules with BRAF and MEK inhibitors showed an improvement in progression-free survival. Otherwise, resistance mechanisms to MAPKinase pathway inhibitors are of interest worldwide. Nevertheless, more fundamental and transversal researches are currently being investigated than validated schedules in daily clinical practice. Following anti-CTLA-4 drugs, second-generation immunotherapies, including anti-PD1 and PD-L1 molecules, confirmed their results in extended cohorts. In the setting of localized melanoma, the final results from MLST-1, Morton's study, regarding the sentinel node procedure versus observation alone, prompted a new enhancement in the sentinel node controversy. From another point of view, "what is not new in oncology in 2014?" In this area, the absence of original investigations on the primary melanoma detection in France and the absence of innovations in the adjuvant treatment of melanoma after surgery should be mentioned. While recent revolutionary drugs, i.e. targeted therapies and immunotherapies, will know advances under the resistance pressure in a near future, a revolution is still awaited in melanoma earlier stages.
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PMID:[What's new in skin cancers?]. 2553 55

Since 2011, the approval of four different classes of novel drugs (the anti-CTLA-4 agent, ipilimumab; BRAF inhibitors [BRAFi]; MEK inhibitors [MEKi]; and the anti-PD-1 drug, pembrolizumab) has revolutionized the care of advanced melanoma, with the disease becoming a model for the development of new treatments for other types of cancer. Further advances in the treatment of melanoma represented some of the key highlights of the European Society of Medical Oncology (ESMO) 2014 congress. The first phase III trial of an anti-PD-1 agent to report the CA209-037 study included 405 patients with metastatic melanoma previously treated with ipilimumab who were randomized 2:1 to receive nivolumab 3 mg/kg every 2 weeks or investigator's choice chemotherapy. Nivolumab was associated with a higher response rate than chemotherapy and was well tolerated, with adverse events mostly low grade and manageable using recommended treatment algorithms. New data on other immunotherapies, namely ipilimumab and pembrolizumab, were also reported. In addition, outside of immunotherapy, combination approaches involving targeted agents were also a major focus of ESMO this year, with two major phase III studies of combined BRAF inhibition and MEK inhibition being reported. Overall, new clinical trial findings reported at ESMO further endorse the view that melanoma, given the continued development of novel, effective compounds, can accurately be described as the most "dynamic" field of oncology at present.
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PMID:Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma. 2554 44

Increasing knowledge on cellular biology has permitted rapid changes in the treatment of metastatic melanoma. Until 2011, dacarbazine was the gold standard treatment at our disposal. In 2011 the treatment landscape changed dramatically with the approval by the FDA of ipilimumab and vemurafenib. These drugs use two new therapeutic approaches: immunomodulation and the targeting of mutated cellular pathways in tumor cells. These two drugs, used as single agents have shown important increases in overall survival, unseen before in patients with advanced melanoma, but are limited by their toxicities and the appearance of acquired resistances. In this article, we review new therapeutic options in pathway-targeted -with the arrival of MEK inhibitors - and immune based melanoma therapies -with the arrival of anti-PD1 and anti-PDL1- as well as new therapeutic strategies developed to overcome acquired resistance and diminish drug toxicities.
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PMID:New treatments for cutaneous metastatic melanoma: MAPK pathway-targeted and immune based therapies. 2555 38

Until recently, a treatment for advanced melanoma with a tolerable side effect profile has remained elusive. Therefore, despite its relatively rare occurrence, melanoma continues to cause the majority of skin cancer deaths, with less than 15% of those affected with late-stage disease surviving 10 years or more. Historically, the mainstay of treatment has been single-agent chemotherapy or immunotherapy with the alkylating agent dacarbazine and interleukin-2 or interferon. Cytotoxic chemotherapy with dacarbazine demonstrated poor response rates and little or no survival benefit, whereas IL-2 and interferon, although showing durable responses, are associated with poor side effect profiles (1, 2). However, with the elucidation of the molecular biology and oncogenic pathways involved in melanoma, agents targeted against mutations in the mitogen-activated protein kinase (MAPK) pathway including BRAF and MEK inhibitors have demonstrated prolonged survival and more manageable side effect profiles relative to traditional chemotherapy. Simultaneously, an evolved understanding of the immunologic basis for the development and regression of melanoma lead to the discovery of immune checkpoint inhibitors, which confer a similar survival benefit. Foremost among these was ipilimumab, a monoclonal antibody against the negative regulatory checkpoint molecule cytotoxic T-lymphocyte protein 4 (CTLA-4), which was the first drug in the management of metastatic melanoma to confer a survival benefit. However, treatment is complicated by a high rate of grade 3 and 4 immune-related adverse events and limited response. Nivolumab, a fully human monoclonal antibody against programmed cell death protein 1 (PD-1), has shown a survival benefit in an open-label phase II trial, and was the first PD-1 inhibitor to be approved worldwide. With a favorable side effect profile and ongoing trials in combination with extant therapies, nivolumab shows substantial potential to further augment the options for an effective treatment in malignant melanoma.
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PMID:Nivolumab. 2558 84

The last decade has spawned an exciting new era of oncotherapy in dermatology, including the development of targeted therapies for metastatic melanoma and basal cell carcinoma. Along with skin cancer, deregulation of the PI3K-AKT-mTOR and RAS-RAF-MEK-ERK intracellular signaling pathways contributes to tumorigenesis of a multitude of other cancers, and inhibitors of these pathways are being actively studied. Similar to other classes of targeted therapies, cutaneous adverse effects are among the most frequent toxicities observed with mitogen-activated protein kinase pathway inhibitors, PI3K-AKT-mTOR inhibitors, hedgehog signaling pathway inhibitors, and immunotherapies. Given the rapid expansion of these families of targeted treatments, dermatologists will be essential in offering dermatologic supportive care measures to cancer patients being treated with these agents. Part II of this continuing medical education article reviews skin-related adverse sequelae, including the frequency of occurrence and the implications associated with on- and off-target cutaneous toxicities of inhibitors of the RAS-RAF-MEK-ERK pathway, PI3K-AKT-mTOR pathway, hedgehog signaling pathway, and immunotherapies.
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PMID:Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways. 2559 39


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