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| Status |
Public on Aug 03, 2023 |
| Title |
Androgen Receptor is a Determinant of Melanoma BRAFi/MEKi Resistance [Clariom_2] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The majority of BRAFV600 mutant melanomas regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). Yet nearly all relapse within the first two years. Most BRAFi/MEKi-resistant tumors are cross-resistant to immunotherapies, highlighting the need to prevent and circumvent resistance. We recently showed that androgen receptor (AR) activity is required for sustained melanoma cells proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells already at very early times of BRAFi exposure. Proliferation and tumorigenicity of BRAFi resistant melanoma cells are blunted by genetic or pharmacologic suppression of AR activity, while AR overexpression is by itself sufficient to rendersmelanoma cells BRAFi/MEKi-resistant. Increased AR elicits transcriptional changes linked with AXL-positive BRAFi resistant subpopulations and induces expression of PAI-1 and EGFR, two determinants of melanoma progression that associate with elevated AR expression in clinical cohorts. Our results point to increased AR signaling as a determinant of melanoma BRAFi resistance, which can be counteracted by AR as well as PAI-1 and EGFR inhibitors.
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| Overall design |
Five different BRAF resistant (BR) melanoma cell lines were established from the parental (P) cells (A375, M121224, M160915, UACC903 and WM9) by continuous culturing in Dabrafenib for a period of 4 weeks, with weekly multistep increases in concentration from 0.5 to 3uM. Parental (P) and BRAF resistant (BR) melanoma cells were collected for transcriptoomic analysis from confluent 10cm dishes. mRNA was extracted using Direct-Zol RNA MiniPrep kit.
Cell line identifier followed by a indication of BRAF resisitant (BR) or parental (P) conditions.
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| Contributor(s) |
Samarkina A, Youssef MK, Dotto GP |
| Citation(s) |
37838724 |
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| Submission date |
May 17, 2023 |
| Last update date |
Oct 26, 2023 |
| Contact name |
Paola Ostano |
| Organization name |
Fondazione Edo ed Elvo Tempia
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| Street address |
via Malta 3
|
| City |
Biella |
| ZIP/Postal code |
13900 |
| Country |
Italy |
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| Platforms (1) |
| GPL23126 |
[Clariom_D_Human] Affymetrix Human Clariom D Assay [transcript (gene) version] |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE232697 |
Androgen Receptor is a Determinant of Melanoma BRAFi/MEKi Resistance |
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| Relations |
| BioProject |
PRJNA973594 |
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