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| Status |
Public on Jun 06, 2021 |
| Title |
Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Disruption of the MAPK pathway in cancer by kinase inhibition often fails due to pathway reactivation, causing clinical relapse. Among MAPK inhibitors, type I RAF inhibitors are only active against specific BRAF mutants; MEK inhibitor monotherapy is associated with limited clinical benefits but may serve as a foundation for combinatorial therapy. Here, we show that type II RAF plus allosteric MEK inhibitors durably blunt the development of acquired MEK inhibitor resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600 and BRAFV600 mutations, when compared to a combination of type II RAF plus ERK inhibitors. Type II RAF and MEK (versus ERK) inhibitors also display superior capacity to sequester MEK in RAF complexes and uncouple MEK and ERK interaction in acquired resistant tumor subpopulations. Systemically and intratumorally, type II RAF plus MEK inhibitors expand memory and activated/exhausted CD8+ T-cells. Whereas trametinib alone temporally reduces dominant intra-tumoral T-cell clones, type II RAF inhibitor co-treatment reverses this effect and promotes T-cell clonotypic expansion and convergence. Importantly, durably control of tumors by this combination requires CD8+ T-cells. Thus, the prolonged anti-tumor efficacy of type II RAF plus MEK inhibitors reveals exquisite MAPK addiction in common lethal cancer histologies, and the mechanisms include unexpected allosteric perturbation of the MAPK pathway and engagement of anti-tumor CD8+ T-cell immunity.
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| Overall design |
This dataset contains the RNA-seq of human melanoma PDXs and cell lines sensitive/resistant to the MEK inhibitor
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| Contributor(s) |
Hong A, Piva M, Liu S, Hugo W, Lomeli SH, Zoete V, Randolph C, Yang Z, Wang Y, Sun L, Vega-Crespo A, Garcia AJ, Shackelford D, Dubinett S, Scumpia PO, Tackett AJ, Donahue TR, Michielin O, Holmen SL, Ribas A, Moriceau G, Lo RS |
| Citation(s) |
33318037 |
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| Submission date |
Sep 27, 2020 |
| Last update date |
Sep 07, 2021 |
| Contact name |
Sixue Liu |
| E-mail(s) |
sxliu0130@gmail.com
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| Organization name |
UCLA
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| Department |
Medicine
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| Street address |
10833 Le Conte Avenue
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| City |
LOS ANGELES |
| State/province |
California |
| ZIP/Postal code |
90064 |
| Country |
USA |
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| Platforms (2) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (33)
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| This SubSeries is part of SuperSeries: |
| GSE158610 |
Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Anti-Tumor T-cell Immunity |
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| Relations |
| BioProject |
PRJNA665977 |
| SRA |
SRP285528 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE158607_RNAseq-combinedCPM.txt.gz |
2.7 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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