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Identification of pathways modulating vemurafenib resistance in melanoma cells via a genome-wide CRISPR/Cas9 screen
- Source :
- G3: Genes|Genomes|Genetics
- Publication Year :
- 2021
- Publisher :
- Oxford University Press, 2021.
-
Abstract
- Vemurafenib is a BRAF kinase inhibitor (BRAFi) that is used to treat melanoma patients harboring the constitutively active BRAF-V600E mutation. However, after a few months of treatment patients often develop resistance to vemurafenib leading to disease progression. Sequence analysis of drug-resistant tumor cells and functional genomic screens has identified several genes that regulate vemurafenib resistance. Reactivation of mitogen-activated protein kinase (MAPK) pathway is a recurrent feature of cells that develop resistance to vemurafenib. We performed a genome-scale CRISPR-based knockout screen to identify modulators of vemurafenib resistance in melanoma cells with a highly improved CRISPR sgRNA library called Brunello. We identified 33 genes that regulate resistance to vemurafenib out of which 14 genes have not been reported before. Gene ontology enrichment analysis showed that the hit genes regulate histone modification, transcription and cell cycle. We discuss how inactivation of hit genes might confer resistance to vemurafenib and provide a framework for follow-up investigations.
- Subjects :
- MAPK/ERK pathway
BRAF-V600E
Brunello library
A375
medicine.disease_cause
AcademicSubjects/SCI01180
CRISPR screen
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Genetics
medicine
Humans
CRISPR
Clustered Regularly Interspaced Short Palindromic Repeats
Vemurafenib
Molecular Biology
Gene
Melanoma
Genetics (clinical)
030304 developmental biology
0303 health sciences
Mutation
biology
Kinase
Mutant Screen Report
Cell cycle
medicine.disease
Histone
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
biology.protein
Cancer research
CRISPR-Cas Systems
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 21601836
- Volume :
- 11
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- G3: Genes|Genomes|Genetics
- Accession number :
- edsair.doi.dedup.....d24f1309af13378f4124164bd4563aa8