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Series GSE107370 Query DataSets for GSE107370
Status Public on Nov 27, 2018
Title Concomitant BCORL1 and BRAF mutations in vemurafenib-resistant melanoma cells
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary BRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFV600E leads to aberrant Ras-independent MAPK signaling and cell transformation. Inhibition of mutant BRAF is a current front-line therapy for such cases, with improved survival compared with chemotherapy. Unfortunately, reactivation of MAPK signaling by several mechanisms has been shown to cause drug resistance and disease recurrence. In this work, we describe the co-occurrence of an in-frame deletion within an amplified BRAFV600E locus, and a missense point mutation of the transcriptional repressor BCORL1, in vemurafenib-resistant A375 melanoma cells. Functional data confirmed that truncated p47BRAFV600E and mutant BCORL1Q1076H both contribute to resistance. Interestingly, either endogenous BCORL1 silencing or ectopic BCORL1Q1076H expression mimicked the effects of a CRISPR/Cas9-edited BCORL1Q1076H locus, suggesting a change-of-function mutation. Transcriptomic data confirmed this hypothesis. Finally, we show that the pan-RAF inhibitor sorafenib is not affected by expression of BRAF deletion variant and effectively synergizes with vemurafenib to block resistant cells, suggesting a possible intervention for this class of mutants.
Overall design Nine total samples: 3 parental plus 3 BCORL1-WT and 3 BCORL1-MUT overexpressing cells
Contributor(s) Mologni L, Piazza R, Massimino L, Gambacorti-Passerini C
Citation(s) 29605720
Submission date Nov 27, 2017
Last update date May 15, 2019
Contact name Luca Massimino
Phone 3389039500
Organization name Ospedale San Raffaele
Department Gastroenterology
Street address Via Olgettina, 58
City Milano
State/province MI
ZIP/Postal code 20100
Country Italy
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (9)
GSM2865572 Parental A375 cells #2
GSM2865573 Parental A375 cells #3
GSM2865574 Parental A375 cells #4
BioProject PRJNA419913
SRA SRP125679

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Supplementary file Size Download File type/resource
GSE107370_RAW.tar 3.0 Mb (http)(custom) TAR (of TAB)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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