BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma

Introduction: BRAF inhibition alone has achieved unprecedented efficacy results in patients affected by BRAF-mutated advanced melanoma. Since these findings, it was postulated that dual inhibition of BRAF and other components of the RAS/RAF/MEK/ERK MAPK pathway (such as MEK) would be superior to BRAF inhibition as monotherapy. A series of recent clinical trials have confirmed this hypothesis.

Areas covered: In this article, the biological rationale for both single and concomitant inhibitions of the MAPK pathway in BRAF mutant melanoma is provided. Moreover, available clinical data on the efficacy and toxicity of BRAF and MEK inhibition as single agents and in combination are extensively reviewed.

Expert opinion: Dual BRAF and MEK inhibition in advanced BRAF-mutated melanoma is superior to single inhibition in terms of efficacy without significant increase in toxicity. Therefore, BRAF plus MEK inhibition is expected to supersede single-agent BRAF inhibition in these patients in the near future.     

Emerging BRAF inhibitors for melanoma

Introduction: The clinical activity of BRAF inhibitor (BRAF-I) therapy is a major breakthrough in the treatment of metastatic melanoma carrying BRAF mutations. However, the therapeutic efficacy of BRAF-I therapy is limited due to the onset of intrinsic and acquired drug resistance.

Areas covered: The role of wild-type BRAF in melanocytes and of the mutated BRAF in the pathogenesis of melanoma is described in this article. The results obtained with BRAF-I in patients with mutated BRAF are reviewed. The mechanisms driving the intrinsic and acquired BRAF-I resistance, the development of combinatorial strategies designed to overcome them and their potential limitations are discussed. Lastly, the many questions that have to be addressed to optimize therapy with BRAF-I are listed.

Expert opinion: Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The discovery of BRAF mutations which drive melanoma tumorigenesis and the development of agents which selectively inhibit mutant-activated BRAF represent a major breakthrough in the treatment of metastatic melanoma. However, the development of drug resistance underlies the need of more effective and individualized combinatorial treatments to counteract the multiple escape mechanisms utilized by BRAF-mutant melanoma. Although combinatorial strategies using agents which target different protumorigenic signaling pathway components have been shown to increase the clinical efficacy of BRAF-I, novel strategies which utilize different antitumor mechanisms are needed.     

New RAF kinase inhibitors in cancer therapy

Introduction: Alterations in some key components of the MAPK pathway, such as BRAF, have been found to be related to the development of several malignancies. A number of BRAF inhibitors have been developed in recent years. Two of these compounds, vemurafenib and dabrafenib, have been licensed for the treatment of BRAF-mutant advanced melanoma.

Areas covered: This article reviews the antitumour activity and safety of the BRAF inhibitors, vemurafenib and dabrafenib. Moreover, early clinical data available for the most promising new members of this family of drugs as well as the novel therapeutic strategy of dual RAF-MEK inhibition is reviewed. A perspective of the potential role of MAPK inhibition in the treatment of cancer in forthcoming years is also provided.

Expert opinion: Inhibition of BRAF has achieved highly successful results in patients affected by BRAF-mutated melanoma and has revolutionised their care. Its efficacy in other malignancies is currently under evaluation in monotherapy and as combination with other agents. Early clinical results of concomitant inhibition of BRAF and MEK suggest that this therapeutic approach is superior to either BRAF or MEK inhibition alone. Identification of BRAF mutations sensitive to treatment is essential for the success of these drugs.     

PLX4032: does it keep its promise for metastatic melanoma treatment?

Importance of the field: Activating mutations in the BRAF kinase gene have been identified in 50% of all melanomas. PLX4032, a selective and potent inhibitor of BRAF V600E mutant tumor cells, has shown inhibition of tumor growth in cell lines harboring BRAF V600E mutations. Data from early clinical trials showed promising results in the treatment of patients with metastatic melanoma.

Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on PLX4032 to evaluate the existing data in both preclinical and Phase I–II studies.

What the reader will gain: The review comprises the rationale for choosing a selective BRAF inhibitor for certain types of melanoma, its mode of action, associated toxicities and potential pitfalls.

Take home message: Despite the convincing response rates in Phase I trials, duration of tumor response is limited in some patients, and a cure cannot be expected. Intrinsic and acquired PLX4032 resistance still has to be investigated; signaling pathway switching is probably the most important factor for development of resistance. Combination therapy with simultaneous inhibition of different pathways might be more effective and warrants further investigation. The toxicity profile of PLX4032 is considerably low, and special attention is needed to address the development of keratoacanthomas and cutaneous squamous cell carcinomas.     

BRAF and MEK inhibition in melanoma

Introduction: Selective inhibition of the MAPK pathway with either BRAF or MEK inhibition has emerged as a key component for the treatment of BRAF-mutant metastatic melanoma. New evidence suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival, while potentially attenuating some of the serious adverse events observed with monotherapy.

Areas covered: This review covers the current data on the efficacy and safety of the selective BRAF (vemurafenib and dabrafenib) and MEK (trametinib) inhibitors as well as the available data on BRAF inhibitor + MEK inhibitor combination therapy (dabrafenib + trametinib and vemurafenib + cobimetinib). The efficacy, safety and toxicity data are discussed from Phase I, Phase II and Phase III trials of these drugs.

Expert opinion: Combination therapy with the BRAF and MEK inhibitors improves response rates and progression-free survival in patients with BRAF-mutant metastatic melanoma. Some of the serious adverse events, in particular, the incidence of cutaneous squamous cell carcinoma, are attenuated with combination therapy, whereas milder side effects such as pyrexia can be more common with combination therapy. Although dose reductions and dose interruptions are slightly more common with combination therapy, overall data supports the notion that combination therapy is safe and improves the outcomes for patients compared to single agent BRAF inhibitors.     

BRAF and MEK inhibitors in pediatric glioma: new therapeutic strategies,new toxicities

Introduction: BRAF mutation was initially reported in metastatic melanomas, and more recently in a variety of human cancers. BRAF acts as a down-stream effector of growth factor signaling leading to cell cycle progression, proliferation and survival. Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma.

Areas covered: Mechanisms of resistance to BRAF inhibitors have recently been described as due to the paradoxical activation of the MAPK pathway. Combination therapy with BRAF and MEK inhibition has proved capable of overcoming the resistance with effective results in patients with melanoma. Prospective studies in pediatric glioma are warranted. Combination therapy has a different toxicity profile compared to BRAF inhibitor alone. Herein we review the state-of-the-art of toxicities associated with these agents, with a special focus on children.

Expert opinion: Some toxicities appear more specific to adults, due to a combination of factors, such as patient age and predisposing risk factors. Moreover, it is recommended that the co-administration of BRAF inhibitors and drugs metabolized by the cytochrome P450 system in the liver be avoided, as this can lead to significant complications secondary to pharmacological interactions.     

Protein kinase inhibitors in melanoma

Introduction: The most commonly mutated oncogene identified to date in melanoma is BRAF (～ 50%), an upstream mediator of the mitogen-activated protein kinase (MAPK) pathway. Recently, BRAF-kinase inhibitors as well as MEK-kinase inhibitors were introduced into the clinics.

Areas covered: Substantial Phase II and III clinical trials were searched in patients with advanced melanoma treated with BRAF-kinase inhibitors, MEK-kinase inhibitors and cKIT inhibitors.

Expert opinion: For patients with a BRAF, NRAS or cKIT mutation the treatment with selective, targeted drugs is considered as feasible and results in a high rate of confirmed tumor responses. In patients with BRAF mutation the progression free survival and overall survival is prolonged in patients who were treated with BRAF kinase inhibitors or MEK kinase inhibitors compared to patients receiving chemotherapy with dacarbazine. A major problem is the development of resistance to the inhibitors through multiple different mechanisms. One approach to overcome resistance is to combine BRAF and MEK inhibitors. Treatments with kinase inhibitors are more efficacious than chemotherapies, however, they compete with the newly developed immune checkpoint blockers, and may in future be preferentially applied in second- or x-line.     

Can binimetinib,encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?

Introduction: Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations.

Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT.

Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.     

Dabrafenib for the treatment of melanoma

Introduction: Approximately 50% of patients with cutaneous melanoma have an activating mutation in BRAF kinase, leading to constitutive activation of the mitogen-activated protein kinase pathway and unregulated cell growth. Selective inhibitors of the mutated BRAF kinase produce response rates of approximately 50% with median progression-free survival of 6 – 7 months. BRAF-blocking therapies work rapidly, with responses seen within 2 weeks after therapy initiation, and they are associated with generally mild toxicities. The BRAF inhibitor dabrafenib recently was approved for use in patients with BRAF V600-mutated metastatic melanoma.

Areas covered: This article discusses the mechanisms of action and pharmacokinetic and pharmacodynamic changes as well as clinical efficacy and safety of dabrafenib for treatment of patients with advanced melanoma including unresectable stage IIIc and stage IV patients who harbor a BRAF V600 mutation. Clinical trial data are reviewed, and efficacy of dabrafenib in patients with brain metastases and in combination with the MEK inhibitor trametinib is discussed.

Expert opinion: Despite rapid and significant tumor reduction in a majority of patients with BRAF-mutant metastatic melanoma who are treated with dabrafenib, this drug’s use as a single agent is limited because of its relatively short duration of response. Various combinations with drug(s) inhibiting other target kinases and/or with immunomodulating agent(s) will likely be the standard in the near future.     

Baohuoside-I suppresses cell proliferation and migration by up-regulating miR-144 in melanoma

Context: Baohuoside-I was reported to induce apoptosis in non-small-cell lung cancer and inhibit the growth of multiple myeloma cells. The antitumour potential of baohuoside-I has not been demonstrated in melanoma yet.

Objective: To investigate the potential antitumour activity of baohuoside-I against melanoma and elucidate its underlying molecular mechanism.

Materials and methods: Cell viability was evaluated by MTT assay. The malignant invasion capacity was measured with trans-well assay. The relative expression change of microRNAs was profiled with microarray. TargetScan was utilized for prediction of target gene of miR-144. Regulatory effect of miR-144 on SMAD1 was determined by dual luciferase reporter assay. Endogenous SMAD1 protein in response to ectopic expression of miR-144 was determined by immunoblotting. Xenograft mice were employed to evaluate antitumour potential of baohuoside-I (25?mg/kg by tail intravenous injection every two days) in vivo.

Results: Baohuoside-I significantly inhibited proliferation (45?±?4% reduction in M14 and 35?±?3% reduction in MV3 at 24?h) and migration (70?±?4% reduction in M14 and 72?±?3% reduction in MV3) in melanoma cells. Mechanistically, baohuoside-I up-regulated miR-144 expression levels (3?±?0.2-fold). Silence of miR-144 reversed the inhibition of baohuoside-I in melanoma. We have identified that SMAD1 was the novel target of miR-144. Moreover, baohuoside-I suppressed melanoma in vivo (52?±?8% reduction in xenograft tumour size at day 20).

Conclusions: Our data suggested significant antitumour potential of baohuoside-I against melanoma both in vitro and in vivo, which warrants further laboratory investigation and clinical trial.     

Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations

Introduction: In the 40–50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.

Areas covered: This article summarizes the mechanism of action of the combination of dabrafenib and trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.

Expert opinion: Combination therapy with dabrafenib and trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less common but side effects such as fever and nausea more common. How dabrafenib/trametinib is best sequenced with other effective treatments such as immune checkpoint blockade remains uncertain.     

Decreased expression of miR-20a and miR-92a in the serum from sulfur mustard-exposed patients during the chronic phase of resulting illness

Abstract

Context: Sulfur mustard (SM), with extensive nucleophilic and alkylating properties, was employed during the Iran–Iraq war by Iraqi forces. The most critical complications attributed to SM are related to dangerous pulmonary disorders collectively known as “mustard lung”. The symptoms gradually emerge over a long period, becoming chronic, and are dependent on time and the amount of exposed SM. Because of the unknown and complex nature of the disease, no differential diagnostic method or absolute treatment strategy has been formally developed.

Objective: The aim of our study was to determine the expression pattern of the microRNAs (miRNAs) miR-92a and miR-20a in the serum of patients with mustard lung along with that of normal individuals. miRNAs have been shown to possess stable persistence in biofluids like plasma and serum and are considered non-aggressive biomarkers helpful for diagnosis and treatment of many diseases.

Materials and methods: A highly sensitive approach called stem-loop real-time quantitative polymerase chain reaction was employed to study the expression of miRNAs. Results: The expression of miR-92a and miR-20a was significantly down-regulated in the serum of patients with mustard lung compared to the control group.

Discussion: Down-regulation of miR-92a and miR-20a may be due to chronic epigenetic alterations after SM exposure, which finally leads to changes in vital cellular processes such as differentiation, proliferation and so forth.

Conclusion: Our findings may provide a differential diagnostic method that is effective for diagnosing lung diseases caused by SM exposure. Additionally, these miRNAs may be regarded as probable targets for treatment of lung injuries.     

MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1

Objectives: We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance.

Design and methods: We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip.

Results: We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change ≥ 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Conclusion: This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor.     

Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation

Introduction: V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma.

Areas covered: This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib.

Expert opinion: Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early-phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.     

New therapies in the treatment of melanoma

Introduction: Therapies targeting immune checkpoints (CTLA-4) and the MAP kinase signaling pathway (RAS/RAF/MEK/ERK) have transformed the treatment of advanced melanoma in the past year. Agents aimed at other therapeutic targets of interest are being actively evaluated in the clinic.

Areas covered: Areas of active therapeutic interest in melanoma include immunotherapy, molecularly targeted therapy and chemotherapy; combinations of these modalities are now under systematic exploration.

Expert opinion: The evaluation of patients with melanoma now includes the molecular profiling of tumor mutations in the BRAF, as well as c-Kit, NRAS and other genes that have been discovered to be drivers of different subsets of the disease. The analysis of the host immunological response to melanoma is equally important, as a basis for the development of immunotherapies that have been of value to melanoma patients in the adjuvant arena, as well as for therapy of metastatic disease. The understanding of these two facets of the disease will provide a more rational basis for the delivery of individualized therapy for the disease both in its advanced setting, and in the adjuvant arena, in the future.     

Vemurafenib for the treatment of melanoma

Introduction: Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib, a BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene.

Areas covered: The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading ‘vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma.

Expert opinion: Vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal-regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research.     

An overview of binimetinib for the treatment of melanoma

ABSTRACT

Introduction

Approximately 50% of patients with metastatic melanoma have mutations in BRAF. Based on the results of prior phase III trials, the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is the standard of care in patients with BRAF-mutant metastatic melanoma.     

Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?

The clinical development of selective BRAF inhibitors for metastatic BRAF V600 mutant melanoma patients has been a major breakthrough in targeted therapeutics. Objective response rates of approximately 50% have been observed in the Phase III studies of the BRAF inhibitors vemurafenib and dabrafenib. The side effects can be relatively common, including proliferative skin toxicities. The latter range from hyperkeratosis and keratoacanthomas (KAs) to squamous cell carcinomas (SCCs) and new primary melanomas. In addition, case reports on the emergence of gastric/colonic polyps and RAS mutant malignancies have been described during BRAF inhibitor therapy. These events have been attributed to paradoxical activation of the MAPK pathway in BRAF wild-type cells exposed to selective BRAF inhibitors in addition to increased RAS activity. Combined BRAF and MEK inhibition appears to improve clinical outcomes and reduce cutaneous proliferation events as fewer KAs and SCCs have been observed with combination therapy. Next-generation pan-RAF inhibitors (‘paradox breakers’) and ERK inhibitors may further enhance clinical activity in metastatic BRAF-mutant melanoma patients and mitigate this paradoxical oncogenesis. Further investigation into the potential long-term effects of selective BRAF inhibitors is warranted as expanded use of these agents is expected in patients with BRAF-mutant melanoma and other malignancies.     

Update on BRAF and MEK inhibition for treatment of melanoma in metastatic,unresectable, and adjuvant settings

Introduction: Selective inhibition of the MAPK pathway with BRAF and MEK inhibitors has emerged as a key component of the treatment of BRAF-mutant unresectable/locally advanced metastatic melanoma.

Areas covered: Current data are presented on the efficacy and safety of BRAFi + MEKi combination therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) from phase I, II, and III trials in the unresectable/locally advanced metastatic setting, as well as neoadjuvant and adjuvant applications. The theoretical basis, pre-clinical findings, clinical trial results and current ongoing clinical studies of combined BRAF/MEK inhibition with immunotherapy, also known as ‘triplet therapy,’ are also explored.

Expert opinion: Combination therapy with BRAF and MEK inhibitors dramatically improves response rates, progression-free survival and overall survival in patients with BRAF-mutant metastatic melanoma compared to historical treatments such as chemotherapy. Some serious adverse effects, including cutaneous squamous cell carcinoma, are attenuated with combination therapy, while less severe and reversible effects including pyrexia, left ventricular dysfunction, and ocular events can be more common with combination therapy. Existing data are insufficient to recommend triplet therapy, or a particular treatment sequence, with respect to BRAF and MEK inhibitors and immune therapies, though results from multiple ongoing trials are anticipated.     

miR-192预测晚期肺腺癌PC方案化疗疗效的价值

目的 探讨晚期肺腺癌患者癌组织中miR-192的表达水平与PC方案化疗疗效的关系。方法 采用qRT-PCR法检测2015年1月至2015年8月安徽医科大学第一附属医院放疗科及化疗科收治的44例晚期肺腺癌患者癌组织中miR-192的表达水平,同时选取相匹配的癌旁组织标本15例作为对照。所有患者接受PC方案化疗,并评价其近期疗效。分析肺腺癌患者癌组织中miR-192的表达水平及癌旁组织中miR-192的表达水平与临床病理特征和PC方案化疗疗效的相关性。结果 癌组织中miR-192的表达水平低于癌旁组织（Z=-2.641,P=0.039）,癌组织中miR-192的表达水平与年龄、性别、ECOG评分、癌组织分化和肝转移无相关性。44例患者均可评价疗效,其中无完全缓解病例、14例部分缓解、20例稳定、10例进展,客观缓解率为31.8%,疾病控制率为77.3%,miR-192的表达水平与化疗疗效呈负相关（r_s=-0.125,P=0.027）。结论 miR-192水平可以预测晚期肺腺癌患者一线PC方案化疗的近期疗效。