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| Status |
Public on Nov 18, 2020 |
| Title |
Adaptive responses to targeted therapy in HER2-positive breast cancer (RNAseq) - TBCRC 036 / LCCC1214 / ClinicalTrials.gov Identifier: NCT01875666 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
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| Overall design |
NOTE: Due to incomplete permissions from participating institutions, we are unable to upload raw data at this time due to patient privacy concerns.
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| Contributor(s) |
Johnson GL, Angus SP |
| Citation(s) |
33980863 |
| Submission date |
Nov 18, 2020 |
| Last update date |
May 10, 2023 |
| Contact name |
Steven P Angus |
| E-mail(s) |
sangus@iu.edu
|
| Phone |
317-274-8911
|
| Organization name |
Indiana University School of Medicine
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| Department |
Pediatrics
|
| Street address |
1044 W Walnut St
|
| City |
Indianapolis |
| State/province |
IN |
| ZIP/Postal code |
46202 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (34)
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| This SubSeries is part of SuperSeries: |
| GSE160670 |
Adaptive responses to HER2-directed therapy in breast cancer cell line models |
|
| Relations |
| BioProject |
PRJNA679284 |
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