Overcoming resistance to BRAF inhibitors

Arozarena, Imanol; Wellbrock, Claudia

doi:10.21037/atm.2017.06.09

Cited by 103 publications

(95 citation statements)

References 143 publications

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“…24 Mechanisms of resistance were fasten on MAPK (mitogenactivated protein kinase) pathway reactivation, gene expression change including acquired overexpression of upstream NRSA and MEK mutations, amplification or alternate splicing of mutant BRAF, reactivation and autophagy of ERK (extracellular regulated protein kinases), 25 COT and MLKs overexpression. 26 Besides, tumor microenvironment change such as microRNA and aryl hydrocarbon receptor (AhR) transcription factor has been found in BRAF resistance. 27,28 Immune microenvironment change such as increasing PD1+ melanoma cells was also related to tumor recurrence.…”

Section: Discussionmentioning

confidence: 99%

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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Background Melanoma is a potentially fatal malignancy with poor prognosis. Several recent studies have demonstrated that combination therapy of BRAF and MEK inhibition achieved better curative effect and appeared less toxic effects. We conducted a meta‐analysis to evaluate the efficacy and safety between BRAF inhibition plus MEK inhibition combination therapy and BRAF inhibition monotherapy in melanoma patients. Methods We performed the search in PubMed, EMBASE, and the Cochrane Library from January 2010 to January 2019. Inclusion and exclusion of studies, assessment of quality, outcome measures, data extraction, and synthesis were independently accomplished by two reviewers. Revman 5.3 software was used for the meta‐analysis. Results Totally, seven randomized controlled trials involving 3146 patients met our inclusion criteria. Comparing the results of combination therapy and monotherapy, combination therapy significantly improved OS (RR = 1.13; 95% CI, 1.08, 1.19; P < 0.00001), ORR (RR = 1.36; 95% CI, 1.28, 1.45; P < 0.00001), PFS (RR = 0.57; 95% CI, 0.52, 0.63; P < 0.00001) and reduced deaths (RR = 0.78; 95% CI, 0.69, 0.88; P < 0.0001). Skin‐related adverse events such as hyperkeratosis, cutaneous squamous‐cell carcinoma were less compared with monotherapy. However, gastrointestinal events like nausea, diarrhea, and vomiting were at a higher frequency. Conclusion Doublet BRAF and MEK inhibition achieved better survival outcomes over single‐agent BRAF inhibition and occurred less skin‐related events, but gastrointestinal events were more in combination therapy.

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Section: Discussionmentioning

confidence: 99%

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Xie

et al. 2019

Cancer Medicine

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“…S4G), the signature genes were partially enriched in GO terms and pathways associated with chemokine signaling (Fig 4B). It has been reported that activated CXC chemokine receptor (CXCR) signaling in melanoma cells contributes to vemurafenib resistance (22,23). Our results indicate that the transcriptional changes in the rep2-2 cluster are distinct from those of the rep1-1 and rep2-1 clusters.…”

Section: Investigation Of Cluster Of Resistance-acquired Cellsmentioning

confidence: 58%

Single-cell analysis of a mutant library generated using CRISPR-guided deaminase

Jun

Lim

Chun³

et al. 2019

Preprint

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CRISPR-based screening methods using single-cell RNA sequencing (scRNA-seq) technology enable comprehensive profiling of gene perturbations from knock-out mutations. However, evaluating substitution mutations using scRNA-seq is currently limited. We combined CRISPR RNAguided deaminase and scRNA-seq technology to develop a platform for introducing mutations in multiple genes and assessing the mutationassociated signatures. Using this platform, we generated a library consisting of 420 sgRNAs, performed sgRNA tracking analysis, and assessed the effect size of the response to vemurafenib in the melanoma cell line, which has been well-studied via knockout-based drop-out screens. However, a substitution mutation library screen has not been applied and transcriptional information for mechanisms of action was not assessed. Our platform permits discrimination of several candidate mutations that function differently from other mutations by integrating sgRNA candidates and gene expression readout. We anticipate that our platform will enable high-throughput analyses of the mechanisms related to a variety of biological events.

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“…4b, c). It has been reported that activated CXC chemokine receptor (CXCR) signaling in melanoma cells contributes to vemurafenib resistance 29,30 . Our results indicate that the transcriptional changes in the rep2-2 cluster are distinct from those of the rep1-1 and rep2-1 clusters.…”

Section: Introduction and Functional Screening Of Putative Mutationsmentioning

confidence: 99%

Single-cell analysis of a mutant library generated using CRISPR-guided deaminase in human melanoma cells

et al. 2020

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CRISPR-based screening methods using single-cell RNA sequencing (scRNA-seq) technology enable comprehensive profiling of gene perturbations from knockout mutations. However, evaluating substitution mutations using scRNA-seq is currently limited. We combined CRISPR RNA-guided deaminase and scRNA-seq technology to develop a platform for introducing mutations in multiple genes and assessing the mutation-associated signatures. Using this platform, we generated a library consisting of 420 sgRNAs, performed sgRNA tracking analysis, and assessed the effect size of the response to vemurafenib in the human melanoma cell line, which has been well-studied via knockout-based drop-out screens. However, a substitution mutation library screen has not been applied and transcriptional information for mechanisms of action was not assessed. Our platform permits discrimination of several candidate mutations that function differently from other mutations by integrating sgRNA candidates and gene expression readout. We anticipate that our platform will enable highthroughput analyses of the mechanisms related to a variety of biological events.

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Overcoming resistance to BRAF inhibitors

Cited by 103 publications

References 143 publications

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

Single-cell analysis of a mutant library generated using CRISPR-guided deaminase

Single-cell analysis of a mutant library generated using CRISPR-guided deaminase in human melanoma cells

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