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| Status |
Public on Dec 01, 2023 |
| Title |
A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Despite the general understanding that different mutations impart different phenotypic changes within a cell, the majority of targeted therapies in cancer treatment are used to treat all mutations in the same gene regardless of location or phenotypic effects. There is a significant unmet need to distinguish distinct changes in cellular signaling which may provide opportunities for mutation-specific treatment with reduced toxicity to patients. Herein, we describe a series of functional genomic analysis with a unique isogenic cell line panel to accurately identify targetable differences between mutations within the same gene. Using an isogenic cell line model bearing two distinct hotspot PIK3CA mutations found in breast cancer, we were able to identify many gene expression and chromatin accessibility differences. These findings allowed us to identify mutation specific molecular targets, specifically AREG as well as a proximal gene regulatory region, that may provide clinically relevant targets. When disrupted, these targets induce a mutation-specific decrease in proliferation and survival in vivo. These findings suggest new mutation-specific modes of treatment for PIK3CA mutant breast cancer and provide a means with which to find mutation-specific targets for the treatment of other oncogenic mutations.
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| Overall design |
The first stage of our discovery platform is the evaluation of the transcriptional environment of isogenic cells bearing either the PIK3CA E545K or H1047R mutation using RNA-seq. The development of this isogenic model was described in Gustin et al 2009 PNAS.
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| Contributor(s) |
Miranda A |
| Citation(s) |
38260414, 38802751 |
| |
| Submission date |
Nov 15, 2023 |
| Last update date |
Jun 12, 2024 |
| Contact name |
Adam Xavier Miranda |
| E-mail(s) |
adam.x.miranda@vanderbilt.edu
|
| Phone |
7045169891
|
| Organization name |
Vanderbilt University
|
| Street address |
2220 Pierce Avenue
|
| City |
Nashville |
| State/province |
TN |
| ZIP/Postal code |
37013 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE247822 |
A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations |
|
| Relations |
| BioProject |
PRJNA1040784 |
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