scholarly journals Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2870 ◽  
Author(s):  
Italia Falcone ◽  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Gianluigi Ferretti ◽  
Francesco Cognetti ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tumor Microenvironment ◽  
Mitogen Activated Protein Kinase ◽  
Acquired Drug Resistance ◽  
Viral Oncogene ◽  
Mitogen Activated Protein ◽  
Melanoma Treatment ◽  
Tumor Types ◽  
Murine Sarcoma ◽  
Viral Oncogene Homolog

Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase kinase (MEK), v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.

scholarly journals Atypical BRAF and NRAS Mutations in Mucosal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1133 ◽  
Author(s):  
Nicolas Dumaz ◽  
Fanélie Jouenne ◽  
Julie Delyon ◽  
Samia Mourah ◽  
Armand Bensussan ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Mucosal Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Nras Mutation ◽  
Viral Oncogene ◽  
Mitogen Activated Protein ◽  
Murine Sarcoma ◽  
Worse Prognosis ◽  
Viral Oncogene Homolog

Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with BRAF and NRAS mutations. We show that in addition to being less frequent, BRAF and NRAS mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the BRAF and NRAS mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical BRAF and NRAS mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.

scholarly journals Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2801
Author(s):  
Ilaria Proietti ◽  
Nevena Skroza ◽  
Nicoletta Bernardini ◽  
Ersilia Tolino ◽  
Veronica Balduzzi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Protein Kinase ◽  
Combination Therapy ◽  
Braf Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Resistance Development ◽  
Viral Oncogene ◽  
Mitogen Activated Protein ◽  
Inhibitor Resistance ◽  
Viral Oncogene Homolog

This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

Mitogen-Activated Protein Kinase Signaling Pathway in Cutaneous Melanoma: An Updated Review

2016 ◽  
Vol 140 (11) ◽  
pp. 1290-1296 ◽  
Author(s):  
Andres Martin Acosta ◽  
ShriHari S. Kadkol
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Cutaneous Melanoma ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Viral Oncogene ◽  
Mitogen Activated Protein ◽  
Viral Oncogene Homolog

The mitogen-activated protein kinase (MAPK) signaling pathway is a cascade of protein kinases that act in a sequential and predominantly linear fashion, albeit displaying some cross talk with other signaling cascades. Mutations in proteins integral to the MAPK signaling pathway are present in more than 50% of cutaneous melanomas. The most frequently mutated protein is v-raf murine sarcoma viral oncogene homolog B (BRAF), followed by neuroblastoma Ras viral oncogene homolog (NRAS). Recently, the development of targeted drugs for the treatment of BRAF-mutant melanoma has led to the widespread implementation of molecular assays for the detection of specific BRAF mutations. There have been some attempts to standardize testing of BRAF mutations, but this has not been achieved so far. Here we provide an updated review on the role of the MAPK signaling pathway in the pathogenesis of cutaneous melanoma, focusing on several different BRAF mutations and their diagnostic and therapeutic implications.

scholarly journals A Rare p.T599dup BRAF Mutant NSCLC in a Non-Smoker

2020 ◽  
Vol 28 (1) ◽  
pp. 196-202
Author(s):  
Alla Turshudzhyan ◽  
James Vredenburgh
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Activating Mutations ◽  
Extracellular Signal ◽  
Activating Mutation ◽  
Mitogen Activated Protein ◽  
Murine Sarcoma

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) mutated non-small-cell lung cancer (NSCLC) is an exceptionally rare form of lung cancer, found only in one to two percent of patients with an NSCLC diagnosis. BRAF NSCLC traditionally affects former or active smokers. BRAF mutations have always been of special interest to the oncological community, as they offer potential for targeted therapies. BRAF mutation spectrum includes mutations that are of both V600 and non-V600 types. BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins such as rapidly accelerated fibrosarcoma (RAF). This makes them susceptible to targeted therapies with RAF inhibitors. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations. While several approaches have been investigated to overcome the limitations of RAF inhibitors, such as use of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) inhibitors or combination of MEK and RAF inhibitors, none of them have been proven to have a superior efficacy for low kinase activity non-V600 BRAF tumors. We present a case of an extremely rare variant of NSCLC BRAF p.T599dup mutation in a non-smoker that responded to a targeted combination therapy with RAF and MEK inhibitors. The patient responded well to therapy that usually targets high kinase activity V600 mutations. Our hope is to bring more attention to non-V600 mutations and document their responses to existing and new therapies.

scholarly journals Treatment of NRAS-mutated advanced or metastatic melanoma: rationale, current trials and evidence to date

2017 ◽  
Vol 9 (7) ◽  
pp. 481-492 ◽  
Author(s):  
Amélie Boespflug ◽  
Julie Caramel ◽  
Stephane Dalle ◽  
Luc Thomas
Keyword(s):  
Metastatic Melanoma ◽  
Cytotoxic Chemotherapy ◽  
Disease Course ◽  
Line Treatment ◽  
First Line ◽  
Viral Oncogene ◽  
Melanoma Patients ◽  
Murine Sarcoma ◽  
Review Current ◽  
Viral Oncogene Homolog

The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1)-mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15–25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment. We will review current preclinical and clinical developments in NRAS-mutated melanoma, and analyze ongoing clinical trials that are evaluating the benefit of different targeted and immune-based therapies, either tested as single agents or in combination, in NRAS-mutant melanoma.

scholarly journals Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study

2018 ◽  
Vol 36 (6) ◽  
pp. 536-542 ◽  
Author(s):  
John D. Hainsworth ◽  
Funda Meric-Bernstam ◽  
Charles Swanton ◽  
Herbert Hurwitz ◽  
David R. Spigel ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Molecular Alterations ◽  
Epidermal Growth ◽  
Tumor Types ◽  
Murine Sarcoma

Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2–amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non–small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

scholarly journals Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

2014 ◽  
Vol 32 (21) ◽  
pp. 2248-2254 ◽  
Author(s):  
Siwen Hu-Lieskovan ◽  
Lidia Robert ◽  
Blanca Homet Moreno ◽  
Antoni Ribas
Keyword(s):  
Targeted Therapy ◽  
Braf Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Braf Inhibitors ◽  
Oncogenic Signaling ◽  
Pathway Activation ◽  
Prolonged Duration ◽  
Trial Testing ◽  
Mitogen Activated Protein ◽  
Braf Mutant

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

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