 |
 |
GEO help: Mouse over screen elements for information. |
|
| 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 |
| E-mail(s) |
admin@lucamassimino.com
|
| 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)
|
|
| Relations |
| BioProject |
PRJNA419913 |
| SRA |
SRP125679 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE107370_RAW.tar |
3.0 Mb |
(http)(custom) |
TAR (of TAB) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...