Current State of Target Treatment in BRAF Mutated Melanoma

Tanda, Enrica T.; Vanni, Irene; Boutros, Andrea; Andreotti, Virginia; Bruno, William; Ghiorzo, Paola; Spagnolo, Francesco

doi:10.3389/fmolb.2020.00154

Cited by 81 publications

(74 citation statements)

References 84 publications

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“…Genetic changes to key molecules in the NRAS/BRAF/MEK pathway lead to reactivation of the previously blocked MAPK pathways or activation of alternative signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway ( Figure 1 ) [ 11 , 36 , 75 , 76 , 77 , 78 ]. In some patients with BRAF inhibitor resistance, the activation of PI3K/AKT is driven by loss of phosphatase and tensin homolog (PTEN) expression [ 79 ].…”

Section: Resultsmentioning

confidence: 99%

“… The MAPK signaling pathway ( A ) in a BRAF inhibitor-sensitive cell showing sites of action of BRAF inhibitors and MEK inhibitors, and ( B ) after BRAF inhibitor resistance development [ 78 ]. Mechanisms of resistance are numbered: (1) upregulation of RTK; (2) BRAF amplification; (3) BRAF alternative splicing; (4) loss of NF1; (6) ERK activation; (7) loss of PTEN; and (8) activation of alternative signaling pathways.…”

Section: Figurementioning

confidence: 99%

“…BRAF, v-Raf murine sarcoma viral oncogene homolog B; ERK, extracellular signal-regulated kinase; GFR, growth factor receptor; mTOR, mammalian target of rapamycin; NF1, neurofibromin 1; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase. From Tanda et al Frontiers in Molecular Biosciences 2020, 7, 154 [ 78 ]. © 2020 Tanda, Vanni, Boutros, Andreotti, Bruno, Ghiorzo and Spagnolo.…”

Section: Figurementioning

confidence: 99%

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

Proietti

Skroza

Bernardini

et al. 2020

Cancers

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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

Proietti

Skroza

Bernardini

et al. 2020

Cancers

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“…However, mainly because of primary and acquired resistance to treatments, the majority of patients will ultimately relapse, and only patients harboring a BRAF mutation, observed in about 50% of cutaneous melanoma, can receive a targeted treatment with BRAF and MEK inhibitors (Spagnolo et al, 2015). The current state of molecular-target drugs and the current therapeutic scenario for patients with BRAF mutated melanoma, from the introduction of BRAF inhibitors as single agents to modern clinical practice, has been extensively described in a related minireview (Tanda et al, 2020). With the purpose of further improving the prognosis of melanoma patients, several preclinical and clinical trials are studying new actionable mechanisms and/or molecules, to simultaneously tackle multiple resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Vanni

Tanda

Dalmasso

et al. 2020

Front. Mol. Biosci.

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Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.

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“…Consistently, analyses of a large cohort of melanoma patients demonstrated that ShcD is a prognostic factor in melanoma. Notably, ShcD silencing sensitizes BRAF-mutant melanoma cells to targeted therapy [ 22 , 23 ], suggesting that the regulation of ShcD expression influences both the cell motility and drug sensitivity of melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma

Aładowicz

Granieri

Marocchi

et al. 2020

Cancers

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Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation of metastatic-specific signaling pathways in the primary melanoma. In the current study, we investigated the role of an adaptor protein of the Shc family (ShcD) in the acquisition of metastatic properties by melanoma cells, exploiting our cohort of patient-derived xenografts (PDXs). We provide evidence that the depletion of ShcD expression increases a spread cell shape and the capability of melanoma cells to attach to the extracellular matrix while its overexpression switches their morphology from elongated to rounded on 3D matrices, enhances cells’ invasive phenotype, as observed on collagen gel, and favors metastasis formation in vivo. ShcD overexpression sustains amoeboid movement in melanoma cells, by suppressing the Rac1 signaling pathway through the confinement of DOCK4 in the cytoplasm. Inactivation of the ShcD signaling pathway makes melanoma cells more sensitive to therapeutic treatments. Consistently, ShcD expression predicts poor outcome in a cohort of 183 primary melanoma patients.

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Current State of Target Treatment in BRAF Mutated Melanoma

Cited by 81 publications

References 84 publications

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

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

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma

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