Concomitant BCORL1 and BRAF mutations in vemurafenib-resistant melanoma cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA419913 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6324400_1.fastq.gz | Fastqsanger.gz | |||
| SRR6324400_2.fastq.gz | Fastqsanger.gz | |||
| SRR6324401_1.fastq.gz | Fastqsanger.gz | |||
| SRR6324401_2.fastq.gz | Fastqsanger.gz | |||
| SRR6324402_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:BRAF targeted drug vemurafenib have shown very good clinical benefit in melanoma patient containing BRAF V600E mutation. However, resistance always occurs in patient. Early stage of the resistance development require the tumor cell adapted to the targeted drug. We are trying to study the kinetic of melanoma cell adaptation towards vemurafenib. 10 melanoma cell lines with BRAF mutation are treated with targeted therapy vemurafenib. RNA-seq samples are collected after drug treatment for different time (day3 and day21) to compare with DMSO-treated control samples for each cell line. Except innate resistant cell line M381, all other cell lines shows inhibition of proliferation. However, a small cluster of cell lines (M397, M229 and M263) shows some other unique transcriptomic change. For cell line M397, M229 and M263, we also collected the RNA-seq data for long-term (73day/90day) drug treatment condition where the cells developed resistance to vemurafenib treatment. Dedifferentiation is enriched in these unique transcriptomic change within these 3 cell lines. Similar cell state dedifferentiation phenomenon is also reported to cause resistance towards immunotherpay where the resistant de-differentiated melanoma cells are induced by TNF which is secreted by tumor-infiltrating T cells. We also treat our cultured melanoma cells with TNF and collected the treated sample for RNA-seq experiment.
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Project description:Vemurafenib is a BRAF inhibitor with specificity for the most common BRAF mutant encountered in melanomas (BRAFV600E). Vemurafenib suppresses the proliferation of BRAF mutant human melanoma cells by suppressing downstream activation of the MEK/ERK mitogen activated protein kinases. We used microarrays to examine the transcriptional response of a vemurafenib-sensitive BRAFV600E human melanoma cell line (A375) to vemurafenib in order to further delineate the mechanisms by which BRAFV600E drives cell proliferation and energy metabolism in human melanoma.
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Project description: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 frontline 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 complex mixture of loss- and gain-of-function effects caused by the 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.
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Project description:Vemurafenib is a BRAF inhibitor with specificity for the most common BRAF mutant encountered in melanomas (BRAFV600E). Vemurafenib suppresses the proliferation of BRAF mutant human melanoma cells by suppressing downstream activation of the MEK/ERK mitogen activated protein kinases. We used microarrays to examine the transcriptional response of a vemurafenib-sensitive BRAFV600E human melanoma cell line (A375) to vemurafenib in order to further delineate the mechanisms by which BRAFV600E drives cell proliferation and energy metabolism in human melanoma. BRAFV600E A375 human melanoma cells were treated with vehicle (0.1% DMSO) or 10 uM vemurafenib for 24 h after which total RNA was extracted. Cells were prepared and RNA was extracted in 3 separate batches (three different cell stocks on three separate days) providing three independent replicates (n=3). Paired replicates (prepared from the same stock of cells on the same day) are denoted by A, B and C.
2014-05-20 | E-GEOD-42872 | biostudies-arrayexpress
Project description:The development of targeted therapies (Braf/MEK inhibitors) and immunotherapy have had a major impact on the treatment of melanoma. However, the majority of patients with advanced melanomas succumb to their disease. The mechanisms of resistance to both targeted therapies and immunotherapies are numerous and have been well-described. These include the alternative acti-vation of Braf/MEK signaling, novel compensating mutations in additional oncogenes, and loss of neoantigens. There has been limited development of small molecules that target alternative path-ways in melanoma in the last two decades. We have previously identified triphenylmethanes as a class that shows activity against a wide variety of tumors. We have synthesized a novel triphenyl-methane, indolium 1, and demonstrated its efficacy against an aggressive vemurafenib-resistant melanoma in vivo. Indolium 1 has a novel mechanism of action against melanoma, in that it results in induction of the tumor-suppressor EphA3. We believe that pre-IND studies are warranted for this novel compound, given its mechanism of action and ability to inhibit the growth of vemurafenib resistant melanoma in vivo
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Project description:The majority of human melanomas bears BRAF mutations and thus is treated with inhibitors of BRAF, such as vemurafenib. While patients with BRAF mutations often demonstrate an initial dramatic response to vemurafenib, relapse is extremely common. Thus, novel agents are needed for the treatment of these aggressive melanomas. Honokiol is a small molecule compound derived from Magnolia grandiflora that has activity against solid tumors and hematopoietic neoplasms. In order to increase the lipophilicity of honokiol, we have synthesized honokiol DCA, the dichloroacetate ester of honokiol. In addition, we synthesized a novel fluorinated honokiol analog, bis-trifluoromethyl-bis-(4-hydroxy-3-allylphenyl) methane (hexafluoro). Both compounds exhibited activity against A375 melanoma in vivo, but honokiol DCA was more active. Gene arrays comparing treated with vehicle control tumors demonstrated induction of the respiratory enzyme succinate dehydrogenase B (SDHB) by treatment, suggesting that our honokiol analogs induce respiration in vivo. We then examined its effect against a pair of melanomas, LM36 and LM36R, in which LM36R differs from LM36 in that LM36R has acquired vemurafenib resistance. Honokiol DCA demonstrated in vivo activity against LM36R (vemurafenib resistant) but not against parental LM36. Honokiol DCA and hexafluoro inhibited the phosphorylation of DRP1, thus stimulating a phenotype suggestive of respiration through mitochondrial normalization. Honokiol DCA may act in vemurafenib resistant melanomas to increase both respiration and reactive oxygen generation, leading to activity against aggressive melanoma in vivo.
2016-01-20 | GSE76956 | GEO
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