Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma

Tomei, Sara; Wang, Ena; Delogu, Lucia Gemma; Marincola, Francesco M.; Bedognetti, Davide

doi:10.1517/14712598.2014.890586

Cited by 20 publications

(17 citation statements)

References 205 publications

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“…About 90% of BRAF mutations consist of a single nucleotide mutation in the 600 codon (V600). Among them, ∼90% of mutations are represented by the valine to glutamic acid substitution (V600E), which is associated with a 400-fold increased activity of the protein, resulting in hyperactivation of the ERK-MAPK pathways [77,[79][80][81][82]. Because of this oncogenic addiction, inhibition of the ERK-MAPK pathway through specific BRAF inhibitors targeting the V600E mutation (i.e.…”

Section: Braf Inhibitionmentioning

confidence: 99%

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

Bedognetti

Roelands

Decock

et al. 2017

Emerging Topics in Life Sciences

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Correspondence: Davide Bedognetti (dbedognetti@sidra.org)With the advent of checkpoint inhibition, immunotherapy has revolutionized the clinical management of several cancers, but has demonstrated limited efficacy in mammary carcinoma. Transcriptomic profiling of cancer samples defined distinct immunophenotypic categories characterized by different prognostic and predictive connotations. In breast cancer, genomic alterations leading to the dysregulation of mitogen-activated protein kinase (MAPK) pathways have been linked to an immune-silent phenotype associated with poor outcome and treatment resistance. These aberrations include mutations of MAP3K1 and MAP2K4, amplification of KRAS, BRAF, and RAF1, and truncations of NF1. Anticancer therapies targeting MAPK signaling by BRAF and MEK inhibitors have demonstrated clear immunologic effects. These off-target properties could be exploited to convert the immune-silent tumor phenotype into an immune-active one. Preclinical evidence supports that MAPK-pathway inhibition can dramatically increase the efficacy of immunotherapy. In this review, we provide a detailed overview of the immunomodulatory impact of MAPK-pathway blockade through BRAF and MEK inhibitions. While BRAF inhibition might be relevant in melanoma only, MEK inhibition is potentially applicable to a wide range of tumors. Context-dependent similarities and differences of MAPK modulation will be dissected, in light of the complexity of the MAPK pathways. Therapeutic strategies combining the favorable effects of MAPK-oriented interventions on the tumor microenvironment while maintaining T-cell function will be presented. Finally, we will discuss recent studies highlighting the rationale for the implementation of MAPK-interference approaches in combination with checkpoint inhibitors and immune agonists in breast cancer.

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Section: Braf Inhibitionmentioning

confidence: 99%

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

Bedognetti

Roelands

Decock

et al. 2017

Emerging Topics in Life Sciences

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“…In the metastatic setting, vaccination strategies have shown some signs of activity [85,86], but results have been overall disappointing with low objective response (OR) rates. Adoptive therapy with TILs is extremely active in melanoma patients [87,88]. However, this approach has not yet been implemented in breast cancer due to the difficulty to generate TIL cultures with specificity against the tumor from which they are generated [89].…”

Section: Checkpoint Inhibitors As Novel Strategies For Breast Cancer mentioning

confidence: 99%

Checkpoint Inhibitors and Their Application in Breast Cancer

et al. 2016

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Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

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“…In the recent years, several molecular alterations have been identified as occurring during melanoma initiation and progression [1,2]. The recognition of driving mutations in multiple melanoma oncogenes allowed the successful implementation of targeted therapies [3]. Perhaps, the most remarkable progress has been made after the identification of BRAF mutations in melanoma [4].…”

Section: Introductionmentioning

confidence: 99%

“…Major advances have been made in the clinical management of melanoma patients carrying BRAF mutations with the adoption of two BRAF specific inhibitors, namely vemurafenib and dabrafenib, approved by the Food and Drug Administration (FDA) in 2011 and 2013, respectively. The correct identification of cancer driving mutations is of paramount importance in cancer diagnostics as this allows the appropriate selection of targeted treatments and the implementation of personalized therapies [3]. To date, several methods are used in diagnostics to identify clinically relevant mutations.…”

Section: Introductionmentioning

confidence: 99%

Differential responsiveness to BRAF inhibitors of melanoma cell lines BRAF V600E-mutated

Hashmi

Konduru

Silcock

et al. 2020

Preprint

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BACKGROUND. Most mutations in melanoma affect one critical amino acid on BRAF gene, resulting in the V600E substitution. Patient management is often based on the use of specific inhibitors targeting this mutation. METHODS. DNA and RNA mutation status were assessed in 15 melanoma cell lines by Sanger sequencing and RNA-seq. We tested the cell lines responsiveness to BRAF inhibitors (vemurafenib and PLX4720, BRAF-specific and sorafenib, BRAF non -specific). Cell proliferation was assessed by MTT colorimetric assay. BRAF V600E RNA expression was assessed by qPCR. Expression level of phosphorylated-ERK protein was assessed by Western Blotting as marker of BRAF activation.RESULTS. Three cell lines were discordant in the mutation detection (BRAF V600E at DNA level/Sanger sequencing and BRAF WT on RNA-seq). We initially postulated that those cell lines may express only the WT allele at the RNA level although mutated at the DNA level. A more careful analysis showed that they express low level of BRAF RNA and the expression may be in favor of the WT allele.We tested whether the discordant cell lines responded differently to BRAF-specific inhibitors. Their proliferation rate decreased after treatment with vemurafenib and PLX4720 but was not affected by sorafenib, suggesting a BRAF V600E biological behavior. Yet, responsiveness to the BRAF specific inhibitors was lower as compared to the control. Western Blot analysis revealed a decreased expression of p-ERK protein in the BRAF V600E control cell line and in the discordant cell lines upon treatment with BRAF-specific inhibitors. The discordant cell lines showed a lower responsiveness to BRAF inhibitors when compared to the BRAF V600E control cell line.The results obtained from the inhibition experiment and molecular analyses were also confirmed in three additional commercial cell lines.CONCLUSION. Cell lines carrying V600E mutations at the DNA level may respond differently to BRAF targeted treatment potentially due to a lower V600E RNA expression.

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Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma

Cited by 20 publications

References 205 publications

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

Checkpoint Inhibitors and Their Application in Breast Cancer

Differential responsiveness to BRAF inhibitors of melanoma cell lines BRAF V600E-mutated

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Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma

Cited by 20 publications

References 205 publications

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

Checkpoint Inhibitors and Their Application in Breast Cancer

Differential responsiveness to BRAF inhibitors of melanoma cell lines BRAF V600E-mutated﻿

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Differential responsiveness to BRAF inhibitors of melanoma cell lines BRAF V600E-mutated