Adaptive responses to HER2-directed therapy in breast cancer cell line models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA673897 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12888214.fastq.gz | Fastqsanger.gz | |||
| SRR12888215.fastq.gz | Fastqsanger.gz | |||
| SRR12888216.fastq.gz | Fastqsanger.gz | |||
| SRR12888217.fastq.gz | Fastqsanger.gz | |||
| SRR12888218.fastq.gz | Fastqsanger.gz |
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Project description: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-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial (ClinicalTrials.gov Identifier: NCT01875666, LCCC1214) designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 transcription factor expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. Patient samples from this trial, when sufficient material was available, were also subjected to kinase enrichment using multiplexed kinase inhibitor bead affinity chromatography and LC-MS/MS. Strongly responsive transcriptional responses observed in a subset of patients corresponded to decreased binding of CDK1 and DDR1 by our proteomic approach. Taken together, our results highlight 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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